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Dual serotonin transporter/histamine H-3 ligands: Optimization of the H-3 pharmacophore
Abstract
A series of tetrahydroisoquinolines acting as dual histamine H3/serotonin transporter ligands is described. A highly regio-selective synthesis of the tetrahydroisoquinoline core involving acid mediated ring-closure of an acetophenone intermediate followed by reduction with NaCNBH3 was developed. In vitro and in vivo data are discussed.
... In this context, Keith and colleagues [30,31] from Johnson & Johnson laboratories described the new symbiotic antidepressant prototype (32), designed by combining pharmacophoric units of the pyrrolidino-tetrahydroquinoline serotonin transporter (SERT) inhibitor (30) [32] and the H 3 Fig. (7). ...
... In this context, Keith and colleagues [30,31] from Johnson & Johnson laboratories described the new symbiotic antidepressant prototype (32), designed by combining pharmacophoric units of the pyrrolidino-tetrahydroquinoline serotonin transporter (SERT) inhibitor (30) [32] and the H 3 Fig. (7). ...
... antagonist JNJ5207852 (31) (Fig. (10)). As anticipated during the planning of this series of hybrid compounds [30], derivative (32) showed to be active on both targets with Ki of 3.3 and 0.7 nM for SERT inhibition and H 3 receptor antagonism, respectively [31]. In vivo microdialysis experiments demonstrated that the elected compound (32) increased expressively the extracellular levels of serotonin and dopamine after intraperitoneal administration of a dose of 1 mg/Kg in rats and, additionally, it exhibited significant effect on 5-hydroxytryptophan potentiated head-twitch model at 3 and 10 mg/Kg (i.p.). ...
Some physiopathological processes involved in the genesis of diseases could suggest the necessity of designing bioligands or prototypes that aggregate, in only one molecule, dual pharmacodynamical properties, becoming able to be recognized by two elected bioreceptors. This approach can have distinct aspects and, when a novel ligand or a prototype acts in two elected targets belonging to the same biochemical pathway, e.g. arachidonic acid cascade, it receives the denomination of dual or mix agent. On the other hand, if these two targets belong to distinct biochemical routes and both are related to the same disease, we can characterize the agents able to modulate it as symbiotic ligands or prototypes. In the present work, we provide some examples and applications of the molecular hybridization concept for the structural design of new symbiotic ligands and prototypes, especially those applied in the treatment of chronic-degenerative disorders.
... We thus asked the question whether we could create a potential antidepressant molecule that would combine the wakepromoting effect of a histamine H 3 receptor antagonist with the serotonin reuptake blockade effects of a SERT inhibitor. The synthetic approach and structure-activity relationships associated with this effort have been described elsewhere ( Keith et al., 2007;Letavic et al., 2007). This paper describes the pharmacology and pharmacokinetics of one such molecule, JNJ-28583867 (2-Methyl-4-(4-methylsulfanyl-phenyl)-7-(3morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline), a novel and selective histamine H 3 receptor antagonist/SERT inhibitor. ...
... We set out to identify and characterize molecules combining both SERT inhibitory and histamine H 3 receptor antagonist activity in a single chemical entity. Several papers have been published detailing the structure-activity relationships of the medicinal chemistry involved in this effort ( Keith et al., 2007; Letavic et al., 2007). One compound, JNJ-28583867, was selected for further profiling. ...
Wake-promoting agents such as modafinil are used in the clinic as adjuncts to antidepressant therapy in order to alleviate lethargy. The wake-promoting action of histamine H(3) receptor antagonists has been evidenced in numerous animal studies. They may therefore be a viable strategy for use as an antidepressant therapy in conjunction with selective serotonin reuptake inhibitors. JNJ-28583867 (2-Methyl-4-(4-methylsulfanyl-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline) is a selective and potent histamine H(3) receptor antagonist (K(i)=10.6 nM) and inhibitor of the serotonin transporter (SERT) (K(i)=3.7 nM), with 30-fold selectivity for SERT over the dopamine and norepinephrine transporters. After subcutaneous administration, JNJ-28583867 occupied both the histamine H(3) receptor and the SERT in rat brain at low doses (<1 mg/kg). JNJ-28583867 blocked imetit-induced drinking (3-10 mg/kg i.p.), confirming in vivo functional activity at the histamine H(3) receptor and also significantly increased cortical extracellular levels of serotonin at doses of 0.3 mg/kg (s.c.) and higher. Smaller increases in cortical extracellular levels of norepinephrine and dopamine were also observed. JNJ-28583867 (3-30 mg/kg p.o.) showed antidepressant-like activity in the mouse tail suspension test. JNJ-28583867 (1-3 mg/kg s.c.) caused a dose-dependent increase in the time spent awake mirrored by a decrease in NREM. Concomitantly, JNJ-28583867 produced a potent suppression of REM sleep from the dose of 1 mg/kg onwards. JNJ-28583867 has good oral bioavailability in the rat (32%), a half-life of 6.9 h and a C(max) of 260 ng/ml after 10 mg/kg p.o. In summary, JNJ-28583867 is a combined histamine H(3) receptor antagonist-SERT inhibitor with in vivo efficacy in biochemical and behavioral models of depression and wakefulness.
... N-Heterocyclic structures as pyridazine, pyrimidine, cytosine and their derivatives attract more importance since some of them are the basic constituents of DNA, RNA and characterize constitutional properties of nucleic acids [3]. Numerous scientists have focused their recent research on the newly synthesized organic moieties that have an impact on various scientific fields as non-linear optics, optoelectronics, and pharmaceutical chemistry as well [4,5]. Constitution properties of pyridazinone derivatives have possessed pharmaceutical antiviral properties including anti-HIV activities [6][7][8][9], antiulcer activities [10], anticancer [11], anticonvulsant [7], cardiotonic and hypotensive [11,12]. ...
We have systematically calculated various physical characteristics such as optimized molecular structural parameters, vibrational frequencies, HOMO-LUMO energy gap, total dipole moment and thermochemical parameters: nuclear repulsion energy, ionization energy, electron affinity, global hardness, electronic chemical potential, global electrophilicity index and finally softness (ζ) using DFT/B3LYP utilizing 6-311G(d,p) basis set for 3-Hydroxy-1-Phenyl-Pyridazin-6(2H)one (HPHP). Also, HPHP nonlinear optical (NLO) properties have been checked by DFT/B3LYP utilizing 6-311G(d,p) basis set. In addition, we have investigated the influence of exposure to UV radiation on HPHP physical properties at the same level of theory. Our results show that HPHP possesses a dipole moment (2.68Debye) and HOMO-LUMO energy gap of 3.99eV that emphasize its high applicability for manufacturing photovoltaic devices such as solar cells. After exposure to UV radiation, the HPHP dipole moment has been lowered from 2.68 to 2.3Debye due to UV radiation. Moreover, a double spin in HPHP has been observed, as electrons are aligned according to their spin state. Electrons (spin ↑) and (spin ↓) are aligned in alpha and beta levels with energy gaps 3.82 and 3.17eV, respectively. This anomalous behavior may be justified by considering that HPHP undergoes anomalous Zeeman-like effect. The presence of this phenomenon in HPHP introduces it as a modern organic semiconductor which has high applicability to be used in modern spintronics.
... Consequently, simpler templates from hexahydropyrroloisoquinoline were attempted, initially, by removal of the fused pyrrolidine ring and one chiral center to obtain the tetrahydroisoquinolines (Letavic et al., 2007a). Structural optimization of tetrahydroisoquinolines derivatives was conducted using a large number of amines in order to improve the binding affinity at H 3 R, varying the physical properties of the resulting compounds and maintaining SERT affinity (Keith et al., 2007b). Several modifications were attempted on the pendant piperidine ring; morpholine and substituted piperidines usually resulted in high affinity compounds. ...
With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.
... A number of syntheses of sertraline have been achieved, but notable work in the area of both the synthesis and pharmacological evaluation of sertraline analogues, as triple reuptake inhibitors, include the research of Shao and co-workers looking into the effect of moving the amine around the tetrahydronaphthalene ring (Fig. 9), 37 and the independent works of Letavic and Middleton on the preparation of selective serotonin reuptake inhibitors. [38][39][40][41][42][43] A structurally related compound, formerly used in the treatment of depression, is nomifensine (Fig. 9). Nomifensine is a chiral 1,1-diarylmethane based on a tetrahydroisoquinoline motif. ...
Compounds containing a 1,1-diaryl motif are numerous, and compounds of this type have found use as catalysts and molecular building blocks, however, this review focusses solely on chiral compounds, wherein the two aromatic rings attached to a central carbon are not identical, and highlights their use and importance as drugs and biologically active molecules.
... Recently series of novel and potent pyrrolidino-tetrahydroisoquinolines with potent dual H 3 antago- nist/SERT inhibitor activity has been reported. The strategies employed for preparation of a dual activity H 3 antagonist/serotonin transporter inhibitor was to introduce an H 3 pharmacophore [78,79] to a known SERT inhibitor [80,81]. ...
For ages, the practice of drug discovery has relied heavily on the one-drug one-target design strategy of me-dicinal chemistry. However, despite the tremendous advances made in chemical and biological sciences and in the discov-ery technologies the number of drugs/drug candidates coming out from this one-drug one-target approach is paradoxically dwindling. It is now well recognized that the age old philosophy of medicinal chemistry lacks a fundamental conceptual framework. This is particularly so in disorders such as depression where a multiple of pathways are simultaneously de-regulated and which basically result from multiple molecular abnormalities, not just from a defect in a single pathway. The recent times has seen a shift towards one drug-multiple target selective design strategy. This novel paradigm has al-ready produced a diverse set of multiple acting structures for depression. Largely as a consequence of the unacceptable side effects, tolerability and low level of efficacy of the currently used drugs (tricyclic antidepressants, mono amine oxi-dase and selective serotonin reuptake inhibitors), other new generation agents are increasingly being identified that act at more than one target in depressive disorders. Multitarget selective antidepressant research has produced a number of di-verse and novel chemistries with a huge potential for the treatment of this debilitating disorder. This manuscript reviews the latest developments surrounding multitarget selective agents for depression, the benefits of such multi acting agents and the implications for the future design of potent and selective dual, triple or even poly-target active antidepressants.
... The receptor and ligands were analyzed the active site for hydrogen bond donors, acceptors, and hydrophobes. The results of the calculation were interaction maps31, 33, 34, 35, 36. ...
To explore the potent inhibitor from one of the Traditional Chinese medicine (TCM), Epimedium sagittatum.
We predicted the potent compound, ES03b, de novo evolution from the four Epimedium sagittatum components were verified by molecular docking, pharmacophore analysis, and analysis of quantitative structure-activity relationship (QSAR) model, which was constructed by multiple linear regression.
ES03b was chosen to undergo drug modification via de novo evolution. By analyzing the pharmacophore features, we found that the hydrophobic core in the binding site and the hydrogen bond generated at Asn663 played key roles in designing PDE5 inhibitors. ES03b generated 49 diversities (Evo01-49). Evo48 had high activity in prediction. Although the value of prediction was overestimated, Evo48 was suggested as the potent lead.
In this study, we showed that the hydrophobic core in the binding site and hydrogen bond production on Asn663 played key roles to design PDE5 inhibitors. From several require validation analysis, Evo48 was suggested to be a potent inhibitor.
... Overlapping fragments derived from H 3 R antagonists (piperidinepropoxyphenyl scaffold), SSRIs (amino-tetrahydronaphthalene from sertraline), and wake-promoters (diphenylmethyl moiety from modafinil) 171) leads to a series of compounds with tetrahydroisoquinoline and naphthyridine pharmacophores, respectively. Derivatisation of the H 3 R affine piperidine, 172) spacer rigidisation, 173) enlargement of the tetrahydroisoquinoline by annelating pyrrolidine, 174) and modifications of the diphenylmethyl substitution pattern 175) result in a great variety of substances. SAR show that JNJ-2853867, a 1,2,3,4-tetrahydroisoquinoline derivative, is the most promising compound. ...
Within the recent years novel lead optimisations for histamine H(3) receptor antagonists made their way from bench to bedside. Structure-activity relationships, cross-affinities and side effects as well as pharmacokinetic profiling will be discussed on selected promising compound series. Due to diversity in potential therapeutic applications and in some cases a controversial debate, different indications will be highlighted with the potential and the problems of the test compounds, e.g. sleep-wake disorders, attention-deficient hyperactivity disorder, epilepsy, cognitive impairment, schizophrenia, obesity and neuropathic pain. First data published on clinical trials phase II (IIb) are presented showing proof of concept of H(3) receptor antagonists in narcolepsy and photo-induced epilepsy.
... This was not surprising, considering that the R 3 groups utilized for this study were the better groups from our previous work. [8][9][10][11] A variety of histamine H 3 pharmacophores were used in this work and the H 3 affinity varies for these compounds. For the alkynes 12, compounds 12v and 12w are poor ligands as are the piperazine 12q and the diazepine 12x. ...
The design, synthesis, and in vitro activity of a series of novel 5-ethynyl-2-aryloxybenzylamine-based histamine H(3) ligands that are also serotonin reuptake transporters is described.
This chapter shows that tetrahydroisoquinolines (THIQs) can be classified as privileged structures that cross over into multiple therapeutic indications. There are a few THIQ small-molecule Food and Drug Administration (FDA)-approved drugs on the market. Quinapril, is marketed by Pfizer under the trade name Accupril, was discovered at Warner-Lambert as an angiotensin-converting enzyme inhibitor for the treatment of hypertension. Chinese researchers published several articles on the design, synthesis, and biological activity of ortho-chlorophenyl tetrahydro isoquinolines and amino acids-linked THIQs as antithrombotic and antiplatelet aggregation agents. N-Methyl-d-aspartate (NMDA) receptor antagonists are potential therapeutic agents for diseases associated with acute and chronic neuronal excitotoxicity such as a focal ischemia, epilepsy, and Parkinson's disease (PD). The Pictet-Spengler reaction is a commonly used synthetic tool for the preparation of THIQs. Masked carbonyls can be employed as equivalents of the carbonyl component in the Pictet-Spengler reactions.
A synthetic route towards 1-t-butoxycarbonyl-3-fluoro-3-methylpyrrolidine and 1-tbutoxycarbonyl 3-fluoro-3-methylazetidine, which are interesting building blocks for pharmaceutical compounds, is described. The key steps include a bromofluorination of appropriate alkenyl azides, followed by reduction to the corresponding amines and subsequent cyclization, yielding the 3-fluorinated azaheterocycles.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
The histamine H3 receptor (H3 R) is an important modulator of numerous central control mechanisms. Novel lead optimizations for H3 R antagonists/inverse agonists involved studies of structure-activity relationships, cross-affinities, and pharmacokinetic properties of promising ligands. Blockade of inhibitory histamine H3 autoreceptors reinforces histaminergic transmission, while antagonism of H3 heteroreceptors accelerates the corticolimbic liberation of acetylcholine, norepinephrine, glutamate, dopamine, serotonin and gamma-aminobutyric acid (GABA). The H3 R positioned at numerous neurotransmission crossroads indicates therapeutic applications of small-molecule H3 R modulators in a number of psychiatric and neurodegenerative diseases with various clinical candidates available. Dual target drugs displaying H3 R antagonism/inverse agonism with inhibition of acetylcholine esterase (AChE), histamine N-methyltransferase (HMT), or serotonin transporter (SERT) are novel class of procognitive agents. Main chemical diversities, pharmacophores, and pharmacological profiles of procognitive agents acting as H3 R antagonists/inverse agonists and dual H3 R antagonists/inverse agonists with inhibiting activity on AChE, HMT, or SERT are highlighted here.
A small series of histamine H3 receptor (H3R) ligands (1-5) incorporating different antiepileptic structural motifs has been newly synthesized. All compounds exhibited moderate to high in vitro hH3R affinities up to a sub-nanomolar concentration range with pKi values in the range of 6.25-9.62 with varying preferences for this receptor subtype. The compounds (1-5) were further investigated in vivo on anticonvulsant effects against maximum electroshock (MES)-induced and pentylenetetrazole (PTZ)-kindled convulsions in rats having phenytoin (PHT) as the reference antiepileptic drug (AED). Surprisingly, animals pretreated with 1 mg/kg, i.p. of 5,5-diphenyl-3-(3-(piperidin-1-yl)propyl)imidazolidine-2,4-dione (4) were only moderately protected and no protection was observed for compounds 1-3 and 5 in three different doses (1 mg, 5 mg, and 10 mg/kg i.p.). Compound 4 (1 mg/kg, i.p.) failed to modify PTZ-kindled convulsion. However, a dose of 10 mg/kg significantly reduced convulsions in both models. In contrast, 5,5-diphenyl-3-(4-(3-(piperidin-1-yl)propoxy)benzyl)imidazolidine-2,4-dione (5) (1, 5, and 10 mg/kg, i.p.) showed proconvulsant effects in the MES model with further confirmation of these results in the PTZ model as no protection was observed against convulsion in the doses tested (1 and 10 mg/kg). In addition, compound 4 (10 mg/kg, i.p.) significantly prolonged myoclonic latency time and shortened total convulsion duration when compared to control, PHT or standard H3R inverse agonist/antagonist pitolisant (PIT). Our results showed that H3R pharmacophores could successfully be structurally combined to antiepileptic moieties, especially phenytoin partial structures, maintaining the H3R affinity. However, the new derivatives for multiple-target approaches in epilepsy models are complex and show that pharmacophore elements are not easily pharmacologically combinable.
H3 antagonists can function to increase the release of various neurotransmitters, including histamine, acetylcholine, norepinephrine, serotonin and dopamine. They have potential utility in addressing a variety of CNS disorders, including deficits in wakefulness and attention, attentiondeficit hyperactivity disorder (ADHD), various dementias, schizophrenia and obesity. The search for H3 antagonists with drug-like properties has been almost exclusively focused on amine-based compounds. These tertiary amine scaffolds exhibit an extremely broad diversity of structural classes and pharmacophores, and demonstrate an inherent tolerance of the H3R to accommodate considerable functional substitutions with large lipophilic aryl groups, polar hydrogen bond donor and acceptor groups or additional basic amines, accounting for the variety and often simplicity of H3 scaffolds. Moreover, drug-like tertiary amines with reduced side effect liabilities have been identified and advanced into clinical evaluation. Many excellent reviews have been recently published on H3 chemistry and biology. An important aspect in understanding the H3R and its ligands is the high degree of constitutive activity in vitro and in vivo.
Antagonists/inverse agonists for the histamine H3 receptor (H3R) are subject to intensive research. Many chemical classes contain a 3-propoxy linker to connect an aromatic moiety and a basic amine. Rigidifying this linker by several moieties has proven successful. However, so far, a 3-cyclobutoxy constraint has not been disclosed in H3R research. Here, we present novel synthetic methodology toward compounds with this functionality. A condensation between piperidine and 1,3-cyclobutanedione followed by a reduction furnishes a versatile cis-3-piperidino-cyclobutanol building block which allows ready access to constrained compounds having a 3-piperidino-cyclobutoxy moiety. Pharmacological studies reveal that this particular rigidification leads to a significant increase in H3R affinity compared to the non-constrained counterpart. In all, the constrained 3-cyclobutoxy linker emerges as a novel, versatile and attractive motif for H3R ligands.
A synthetic route toward new 1-alkyl-3-aminomethyl-3-fluoropiperidines, which are of high interest as building blocks in medicinal chemistry, is described. The Successful approach consists of the fluorination of ethyl 3-chloropropyl-2-cyanoacetate with N-fluorodibenzenesulfonimide (NFSI) and transformation of the ester moiety into different amides, yielding N-alkyl-5-chloro-2-cyano-2-fluoropentanamides. Ring closure was achieved under basic conditions, yielding 1-alkyl-3-fluoro-2-oxopiperidine-3-carbonitriles. After reduction of the obtained lactams with borane, the desired 3-aminomethyl-3-fluoropiperidines were obtained in good yields.
An efficient synthesis of compound 1 featuring a novel sequential Friedel–Crafts alkylation strategy to construct the 4-aryl-tetrahydroisoquinoline core structure has been developed. Resolution with (d/l)-di-p-toluoyl-tartaric acid is utilized to provide the enantiomerically pure material. Overall, the route is concise and amenable for large-scale synthesis.
A facile, moderate to high yielding synthesis of hexahydro-(di)-benzazocinones is described via an intramolecular N-acyliminium ion cyclisation. The iminium ion intermediates are formed from the readily available 4,4-diethoxybutyl amides with an excess of triflic acid. For electron-withdrawing substituents, better yields were obtained from the pre-formed 2-hydroxypyrrolidine amides. From NMR studies, at ambient temperatures the pyrrolo-benzazocin-3-ones exist as a slowly equilibrating mixture of two conformations.
Two isomeric conformationally restricted analogues of 4 trifluoromethylpiperidine were designed. The synthesis was performed in four steps from commercially available N-benzyl maleimide. The key reaction was the [3+2]-cycloaddition between trifluoromethyldiazomethane and N-benzyl maleimide.
In continuation of the investigation of 1-dialkylaminoethyl-2,3-dihydroimidazo[1,2-a]benzimidazoles demonstrating serotoninergic activity, several new substances of this class with 4-substituted piperazines
and piperidines as amine moieties were synthesized and tested pharmacologically in vitro. All substances were investigated for antiserotoninergic, antiplatelet, haemorheological, antiarrhythmic, and antioxidant
activity.
Key wordssynthesis-2,3-dihydroimidazo[1,2-a]benzimidazoles-antiserotonin activity-heamorheological properties-antiarrhythmic activity-antiplatelet activity
A series of compounds was designed as dual inhibitors of the H(3) receptor and the norepinephrine transporter. Compound 5 (rNET K(i) = 14 nM; rH(3)R K(i) = 37 nM) was found to be efficacious in a rat model of osteoarthritic pain.
A short and efficient synthesis of 4-aminomethyl-4-fluoropiperidines and 3-aminomethyl-3-fluoropyrrolidines is described. These fluorinated azaheterocycles are of specific interest as bifunctional building blocks for fluorinated pharmaceutical compounds. The key step of the synthetic pathway involves the regioselective bromofluorination of N-Boc-4-methylenepiperidine and 3-methylenepyrrolidine using Et(3)N.3HF and NBS.
Depression is a major health issue, which is routinely treated with selective serotonin reuptake inhibitors. However, although these agents display a favorable effect on mood, they often fail to improve conditions that accompany depression including cognitive impairment and fatigue. In pre-clinical studies histamine H(3) receptor antagonists have demonstrated both pro-cognitive and wake-promoting effects suggesting that the combination of a histamine H(3) receptor antagonist and a serotonin reuptake inhibitor may have utility as an antidepressant therapy. To this end we sought to introduce histamine H(3) receptor antagonist activity into both known selective serotonin reuptake inhibitors and novel templates. These efforts have afforded several series of compounds with the desired activities. Selected examples demonstrated in vivo efficacy both in pre-clinical models of depression and wakefulness.
The triflic acid-mediated cyclisation of N-arylmethyl- and N-arylethyl-acylpyrrolidinium ions gave moderate to good yields of pyrrolo-tetrahydroisoquinolones and pyrrolo-benzazepinones respectively. Electron-donating R substituents enhanced the rate of reaction and gave higher yields than electron-withdrawing substituents. Substituents on the methyl or ethyl chain in general enhanced the reaction, unless sterically encumbered. The equivalent acylpiperidinium ions cyclised much slower and in lower yield.
Synthetic strategies toward 3-fluoroazetidine-3-carboxylic acid, a new cyclic fluorinated beta-amino acid with high potential as building block in medicinal chemistry, were evaluated. The successful pathway includes the bromofluorination of N-(diphenylmethylidene)-2-(4-methoxyphenoxymethyl)-2-propenylamine, yielding 1-diphenylmethyl-3-hydroxymethyl-3-fluoroazetidine after reduction of the imino bond, ring closure, and removal of the 4-methoxybenzyl group. Changing the N-protecting group to a Boc-group allows further oxidation to 1-Boc-3-fluoroazetidine-3-carboxylic acid, a new fluorinated heterocyclic amino acid.
More and more evidences are still accumulating rapidly on the G-protein-coupled-receptors (GPCRs) dimerization/oligomerization. Such common feature of GPCRs has called extensive attention to both pharmacologists and medicinal chemists for illustration of the pharmacological functions and therapeutic utilities of such receptor complex. Although there is still no clear explanation for the receptor dimerization/oligomerization, a large number of multivalent ligands (MLs) have been designed to target the receptor-dimers/oligomers. Such MLs have gained much acceptance in exploring the receptor complex of dopaminergic, adrenergic, serotoninergic, and opioidic receptor systems, due to the relatively broader experience in recognizing the receptor-dimerization. More and more MLs have also been designed to face GPCR-related very complex neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD) and schizophrenia, which are not effectively treated by traditional highly selective drugs. Herein, some of the most recent developments in this field, as well as some typical examples of MLs, are highlighted, with a particular focus on GPCRs.
A series of novel tetrahydronaphthyridine-based histamine H(3) ligands that have serotonin reuptake transporter inhibitor activity is described. The 1,2,3,4-tetrahydro-2,6-naphthyridine scaffold is assembled via the addition of a nitrostyrene to a metalated pyridine followed by reduction and cyclization to form the naphthyridine. In vitro biological data for these novel compounds are discussed.
A series of novel and potent pyrrolidino-tetrahydroisoquinolines with dual histamine H(3) antagonist/serotonin transporter inhibitor activity is described. A highly regio- and diastereoselective synthesis of the pyrrolidino-tetrahydroisoquinoline core involving acid mediated ring-closure of an acetophenone intermediate followed by reduction with NaCNBH(3) was developed. In vitro and in vivo data are discussed.
The synthesis and structure-activity relationships of a series of novel phenoxyphenyl diamine derivatives with affinity for both the histamine H(3) receptor and the serotonin transporter is described.
Design and synthesis of highly potent and selective non-imidazole inverse agonists for the histamine H-3 receptor is described. The study validates a new pharmacophore model based on the merging of two previously described models. It also demonstrates that the removal of the basic center potentially interacting with ASP3.32 and common to both models leads to loss of activity, whereas the replacement of the second basic center by an acceptor retains the potency. 14 (c) 2007 Elsevier Ltd. All rights reserved.
A series of novel and potent 6-heteroaryl-pyrrolidino-tetrahydroisoquinolines with dual histamine H(3) antagonist/serotonin transporter inhibitor activity is described. In vitro and in vivo data are discussed.
The neurotransmitter histamine exerts its action through four distinct histamine receptors. The histamine H(1) and H(2) receptor are well established drug targets, whereas the histamine H(4) receptor is undergoing rigorous characterisation at present. The histamine H(3) receptor (H(3)R) is a G(i/o)-protein coupled receptor and is mostly expressed in the CNS. A remarkably large and different array of therapeutic areas, in which ligands for the H(3)R may prove useful, has been identified and a massive research undertaking is underway to substantiate the high expectations for H(3)R ligands. At present, several ligands for the H(3)R are being evaluated in clinical studies. In this review, the many potential therapeutic areas for H(3)R antagonists, inverse agonists and agonists is discussed. Promising medicinal chemistry and toxicological developments, as well as the advancement of several H(3)R ligands into the clinic, will be highlighted. This review also describes the problems that have been overcome and the questions that remain in developing H(3)R-related drugs. Considering the tremendous efforts by industry, it can be expected that the first H(3)R drugs will reach the market soon.
A series of tetrahydroisoquinolines acting as dual serotonin transporter inhibitor/histamine H(3) antagonists is described. The introduction of polar aromatic spacers as part of the histamine H(3) pharmacophore was explored. A convergent synthesis of the final products allowing late stage introduction of the aromatic side chain was developed. In vitro and in vivo data are discussed.
The synthesis and biological activity of a new series of piperazine and diazepane amides is described. The new compounds are high affinity histamine H3 ligands and serotonin reuptake inhibitors.
Difluoropiperidines attract considerable interest from organic and medicinal chemists, but their synthesis is often problematic. This paper describes a new synthetic pathway toward valuable 3,3-difluoropiperidines starting from suitable delta-chloro-alpha,alpha-difluoroimines. The latter imines can be synthesized via electrophilic fluorination of the corresponding delta-chloroimines using NFSI (N-fluorodibenzenesulfonimide) in acetonitrile. After hydride reduction of the imino bond and subsequent intramolecular substitution of the chloride atom, new 3,3-difluoropiperidines were obtained in good yields. In addition, this methodology was applied to establish the first synthesis of N-protected 3,3-difluoropipecolic acid, a new fluorinated amino acid.
Worldwide, 340 million people are affected by depression, with high comorbid, social and economic costs.
To identify potential predictors of effect in prevention programmes.
A meta-analysis was made of 69 programmes to reduce depression or depressive symptoms.
The weighted mean effect size of 0.22 was effective for different age groups and different levels of risk, and in reducing risk factors and depressive or psychiatric symptoms. Programmes with larger effect sizes were multi-component, included competence techniques, had more than eight sessions, had sessions 60-90 min long, had a high quality of research design and were delivered by a health care provider in targeted programmes. Older people benefited from social support, whereas behavioural methods were detrimental.
An 11% improvement in depressive symptoms can be achieved through prevention programmes. Single trial evaluations should ensure high quality of the research design and detailed reporting of results and potential predictors.
1,2,3,4-Tetrahyro-2-methyl-4-phenylisoquinolines 6 are obtained from aromatic aldehydes 1, methyl amine and α-haloacetophenones 2 in the presence of sodium borohydride followed by cyclization with sulfuric acid and zinc in methanol.
A theoretical analysis has been made of the relationship between the inhibition constant (KI) of a substance and the (I50) value which expresses the concentration of inhibitor required to produce 50 per cent inhibition of an enzymic reaction at a specific substrate concentration. A comparison has been made of the relationships between KI and I50 for monosubstrate reactions when noncompetitive or uncompetitive inhibition kinetics apply, as well as for bisubstrate reactions under conditions of competitive, noncompetitive and uncompetitive inhibition kinetics. Precautions have been indicated against the indiscriminate use of I50 values in agreement with the admonitions previously described in the literature. The analysis described shows KI does not equal I50 when competitive inhibition kinetics apply; however, KI is equal to I50 under conditions of either noncompetitive or uncompetitive kinetics.
The effects of the histamine H3 receptor agonist, (R)-alpha-methylhistamine were compared with those of the histamine H3 antagonist, thioperamide, in rats implanted with electrodes for chronic sleep recordings. (R)-alpha-Methylhistamine (1.0-4.0 micrograms) injected bilaterally into the premammillary area where histamine immunoreactive neurons have been detected increased slow wave sleep, whereas wakefulness and REM sleep were decreased. No significant effects were observed when (R)-alpha-methylhistamine (1.0-8.0 mg/kg) was administered i.p. Thioperamide (1.0-4.0 mg/kg i.p.) increased wakefulness and decreased slow wave sleep and REM sleep. Pretreatment with thioperamide (4.0 mg/kg) prevented the effects of (R)-alpha-methylhistamine (2.0 micrograms) on slow wave sleep and wakefulness. Our results further support an active role for histamine in the control of the waking state.
A series of pyrrolo[2,1-a]isoquinolines, and related compounds, were examined for antidepressant-like activity, by virtue of their antagonism of tetrabenazine-induced ptosis and sedation, and inhibition of biogenic amine uptake. Thus, we have identified some of the most potent antagonists of TBZ-induced ptosis and some of the most potent inhibitors of the uptake of dopamine, norepinephrine, and serotonin (in rat brain synaptosomes) ever reported. Compounds of particular note, in this regard, are 52b, 29b, 22b, and 48b, respectively. Biological activity was chiefly manifested by the trans isomeric class. Also, through resolution of four compounds, 7b, 24b, 37b, and 48b, biological activity was found to be associated with the (+) enantiomer subgroup (salts measured at 589 nm in MeOH), corresponding to the 6S, 10bR absolute configuration for 7b, 37b, and 48b, and the 6R,10bR configuration for 24b. An X-ray determination on (+)-24b X HBr established its absolute configuration; configurations for the other compounds were verified by enantiospecific synthesis starting with (+)-(R)-2-phenylpyrrolidine. Regarding the pendant phenyl ring, diverse substitution patterns were investigated. Those substitutions that were particularly unfavorable were 3',4',5'-trimethoxy (20b), 2',3',4',5',6'-pentafluoro (34b), 2'-trifluoromethyl (38b), 3',5'-bis(trifluoromethyl) (42b), 4'-n-butyl (44b), 2'-cyano (47b), 4'-methylsulfonyl (50b), and 2'-carboxy (58b). Exceedingly potent compounds, in one way or another, were 10b-12b, 22b, 23b, 25b, 28b, 29b, 33b, 45b, 48b, 51b-53b. The pattern of aromatic substitution had a strong impact on selectivity in the uptake tests (NE vs. DA vs. 5-HT). Activity was significantly diminished by methyl substitution of 7b at the 5 (65, 66), 6 (61b), or 10b (60b) position, by changing the phenyl group of 7b to cyclohexyl (67b), benzyl (68b), or H (72), by moving the phenyl group of 7b to the 5 (69) or 10b (70) position, by expansion of ring B to an azepine (78b), and by modification of ring C to an azetidine (77b), piperidine (75b), or azepine (74b). The interaction of selected analogues with various CNS receptors is reported. Little affinity was shown for the muscarinic cholinergic receptor, suggesting a lack of anticholinergic side effects. Interestingly, 24b and 33b displayed a high affinity for the serotonin-2 receptor, analogous to mianserin and clomipramine. After the body of data was reviewed, derivatives 24b and 48b were chosen for advanced development.
Previously we have shown that cocaine attenuates the 5-HT2A receptor-mediated head-twitch response (HTR) in mice produced by the 5-HT2A/C direct agonist (+/-)-1 (2.5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). This inhibition appears to be due to cocaine-induced indirect stimulation of the inhibitory serotonergic 5-HT1A and noradrenergic alpha 2 receptors via the inhibition of reuptake of synaptic serotonin (5-HT) and norepinephrine (NE), respectively. In the present study, we investigated the effects of cocaine, its phenyltropane analogue WIN 35428, and the selective 5-HT (sertraline). NE (nisoxetine) and dopamine (DA) (GBR 12935) reuptake inhibitors on the 5-hydroxytryptophan (5-HTP)-induced HTR. We utilized two experimental protocols where cocaine or the cited drugs were administered either after (protocol 1) or prior (protocol 2) to 5-HTP injection. Cocaine in both protocols produced a dose-dependent enhancement in the 5-HTP-induced HTR (ED50 4.68 +/- 1.21 and 3.55 +/- 1.31, respectively). Sertraline was more potent (ED50 2.64 +/- 1.1 and 2.1 +/- 1.54, respectively) in enhancing the induced behavior and dose by dose produced greater (3 to 10 times) HTRs than cocaine. On the other hand, nisoxetine dose dependently and completely attenuated the induced behavior (ID50 3.33 +/- 1.32 and 1.72 +/- 1.34, respectively), whereas GBR 12935 only at high doses (ID50 15.34 +/- 1.52 and 11.91 +/- 1.3, respectively) decreased the induced response. The inability of cocaine to induce as many HTRs as sertraline appears to lie in its ability to also indirectly stimulate the inhibitory 5-HT1A and alpha 2 receptors because the stimulant caused greater enhancement in the 5-HTP-induced HTRs in the presence of their corresponding antagonists [S(-)-UH 301 and yohimbine, respectively]. WIN 35428 was more potent (ED50 2.87 +/- 1.3 and 1.79 +/- 1.1 for protocols 1 and 2, respectively) in stimulating the 5-HTP-induced HTR and produced a bell-shaped dose-response curve. The results indicate that cocaine enhances the 5-HTP-induced HTR via the inhibition of synaptic 5-HT reuptake. The stimulant also simultaneously attenuates the induced behavior by indirect simulation of the serotonergic 5-HT1A and noradrenergic alpha 2 receptors via inhibition of reuptake of the corresponding monoamines.
Antidepressants have unequivocal efficacy as compared with placebo, but many patients have residual symptoms despite a robust response to antidepressant therapy. The purpose of this study is to assess residual symptoms in outpatients who respond acutely to fluoxetine.
Two hundred and fifteen outpatients with major depressive disorder as assessed with the Structured Clinical Interview for DSM-III-R (SCID-P) were treated openly with fluoxetine 20 mg/day for 8 weeks. One hundred and eight (50.2%) were considered full responders (final 17-item Hamilton Rating Scale for Depression [HAM-D] score < or =7). Percentages of full responders who continued to have subthreshold or full major depressive disorder symptoms were calculated. The relationship between residual symptoms and Axis I and Axis II (assessed with SCID-II for personality disorders) comorbidity was assessed.
Of the 108 responders, 19 (17.6%) had no subthreshold or threshold SCID-P major depressive disorder symptoms, while 28 (25.9%) had 1 symptom, and 61 (56.5%) had 2 or more symptoms. No statistically significant relationships were found between number of residual symptoms and selected Axis I comorbid conditions or total number of Axis II disorders.
Less than 20% of full responders to fluoxetine by HAM-D criteria were free of all SCID-P subthreshold and threshold major depressive disorder symptoms after 8 weeks of treatment. While depressed patients benefit from antidepressants, most continue to have some symptoms of depression. The high prevalence of residual symptoms among antidepressant responders suggests the need for further study including whether residual symptoms abate with longer treatment or increased dose of fluoxetine. Other strategies, such as cognitive behavioral therapy, may be needed to address residual symptoms.
The first pan-European survey of depression in the community (DEPRES I) demonstrated that 17% of the general population suffer from depression (major depression, minor depression, or depressive symptoms). This article describes findings from a second phase of DEPRES (DEPRES II), in which detailed interviews based on a semi-structured questionnaire (78 questions) were conducted with 1884 DEPRES I participants who had suffered from depression and who consulted a healthcare professional about their symptoms during the previous 6 months. The mean time from onset of depression was 45 months, and the most commonly experienced symptoms during the latest period were low mood (76%), tiredness (73%) and sleep problems (63%). During the previous 6 months, respondents had been unable to undertake normal activities because of their depression for a mean of 30 days, and a mean of 20 days of work had been lost to depression by those in paid employment. Approximately one-third of respondents (30%) had received an antidepressant during the latest period of depression. Significantly more respondents given a selective serotonin reputake inhibitor found that their treatment made them feel more like their normal self than those given a tricyclic antidepressant, and fewer reported treatment-related concentration lapses, weight problems, and heavy-headedness (all P < 0.05). Approximately two-thirds of respondents (70%) had received no antidepressant therapy during the latest period of depression, and prescription of benzodiazepines alone, which are not effective against depression, was widespread (17%). There is a need for education of healthcare professionals to encourage appropriate treatment of depression.
Historically, the emphasis in treating depression has been focused on the acute phase of treatment, with few published data on the continuation and maintenance phases of treatment. Yet the risk of depression increases with each episode, with a 50% to 90% chance of developing another episode after 1 or 2 prior episodes of depression. Moreover, subsequent episodes of depression are often of longer duration, more severe, and less responsive to treatment. Most patients with major depression require some form of long-term antidepressant treatment, and many need lifelong treatment. Optimizing efficacy and minimizing side effects are essential during both the acute and long-term phases of antidepressant treatment. Antidepressant side effects, including insomnia or somnolence, weight gain, asthenia, and sexual dysfunction, can significantly decrease patient compliance with long-term treatment for depression. Identification and management of side effects, combined with early and ongoing educational messages to the patient about treatment issues and the importance of sustaining illness remission, help improve compliance and reduce the potential for premature discontinuation of an otherwise optimal antidepressant.
A 1993 meta-analysis of US Investigational New Drug clinical trials of fluoxetine reinforced this agent's more favorable adverse-event profile compared with tricyclic antidepressants (TCAs).
The present meta-analysis sought to provide a reanalysis of updated adverse-event and discontinuation data for fluoxetine 20 to 80 mg/d compared with TCAs and placebo in the treatment of major depressive disorder (MDD) in adults. A subanalysis to assess the safety profile of the most commonly used effective dose of fluoxetine in MDD (20 mg) was also conducted.
Data were obtained from 25 double-blind clinical trials involving 4016 patients with MDD randomized to treatment with fluoxetine 20 to 80 mg/d, TCAs, or placebo. The subanalysis included data from 6 trials involving 1258 patients treated with fixed 20-mg doses of fluoxetine or placebo. Spontaneously reported treatment-emergent adverse events, reasons for discontinuation, and events leading to discontinuation were compared between groups.
The age of the 4016 randomized patients ranged from 12 to 90 years, with a mean age of 46 years. Most patients were white (92%), and 62% were female. The age of the 1258 patients in the 20-mg fixed-dose population ranged from 18 to 90 years, with a mean age of 54 years; as in the total population, most of these patients were white (92%), and 57% were female. The adverse-event profiles of fluoxetine and TCAs in these trials were consistent with the typical profiles of selective serotonin reuptake inhibitors and TCAs. At a dose of 20 mg/d, fluoxetine-treated patients had a discontinuation rate due to adverse events that was not statistically significantly different from that in placebo recipients. Discontinuation rates due to lack of efficacy were not significantly different between fluoxetine and TCAs. However, significantly more TCA-treated patients discontinued therapy because of adverse events and significantly fewer completed treatment compared with fluoxetine-treated patients (both, P < 0.001). The most common events (> or = 2%) leading to discontinuation were asthenia, dizziness, insomnia, nausea, nervousness, somnolence, and tremor in fluoxetine-treated patients and abnormal vision, agitation, constipation, dizziness, dry mouth, headache, nausea, nervousness, rash, somnolence, sweating, and tremor in TCA-treated patients.
Data from this large series of clinical trials confirm that fluoxetine is well tolerated in the acute treatment of MDD in adults, especially at a dosage of 20 mg/d, and is better tolerated than the recommended doses of TCAs.
Residual symptoms, despite successful response to therapy, appear to be the rule in unipolar depression. Most of the residual symptoms occur in the prodromal phase of illness. Residual symptoms are associated with biological correlates, mainly involving the hypothalamic-pituitary-adrenal (HPA) axis and the sleep architecture. They are powerful predictors of relapse. These findings have led to the hypothesis that residual symptoms upon recovery may progress to become prodromal symptoms of relapse. A sequential strategy (encompassing pharmacotherapy in the acute phase of illness and cognitive behavioral therapy in its residual phase) has been developed and was found to be effective in decreasing relapse rate in controlled studies. A largely untested assumption in unipolar depression is that pharmacological strategies that are effective in the short term are the most suitable for postacute and residual phases or maintenance. The literature on subclinical symptomatology calls for specific, stage-oriented, therapeutic approaches. The efficacy of antidepressant drugs may be assessed not only on differential remission rates, but also on differential amount of residual symptomatology after response.
Continued exploration of the SAR around the lead imidazopyridine histamine H(3) antagonist 1 has led to the discovery of several related series of heterocyclic histamine H(3) antagonists. The synthesis and SAR of indolizine, indole and pyrazolopyridine based compounds are now described.
4-(Aminoalkoxy)benzylamines were prepared and screened for in vitro activity at the human histamine H(3) receptor. Some members of this series exhibited subnanomolar binding affinities. Analogues in which one nitrogen atom was replaced with a methine group showed greatly reduced binding affinities. Six members of this series were found to be antagonists in a cell-based model of human histamine H(3) receptor activation. One member of this series, 1-[4-(3-piperidin-1-ylpropoxy)benzyl]piperidine (7b), was found to be a selective and potent human H(3) receptor antagonist.
1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidine (JNJ-5207852) is a novel, non-imidazole histamine H3 receptor antagonist, with high affinity at the rat (pKi=8.9) and human (pKi=9.24) H3 receptor. JNJ-5207852 is selective for the H3 receptor, with negligible binding to other receptors, transporters and ion channels at 1 μM.
JNJ-5207852 readily penetrates the brain tissue after subcutaneous (s.c.) administration, as determined by ex vivo autoradiography (ED50 of 0.13 mg kg−1 in mice). In vitro autoradiography with 3H-JNJ-5207852 in mouse brain slices shows a binding pattern identical to that of 3H-R-α-methylhistamine, with high specific binding in the cortex, striatum and hypothalamus. No specific binding of 3H-JNJ-5207852 was observed in brains of H3 receptor knockout mice.
In mice and rats, JNJ-5207852 (1–10 mg kg−1 s.c.) increases time spent awake and decreases REM sleep and slow-wave sleep, but fails to have an effect on wakefulness or sleep in H3 receptor knockout mice. No rebound hypersomnolence, as measured by slow-wave delta power, is observed. The wake-promoting effects of this H3 receptor antagonist are not associated with hypermotility.
A 4-week daily treatment of mice with JNJ-5207852 (10 mg kg−1 i.p.) did not lead to a change in body weight, possibly due to the compound being a neutral antagonist at the H3 receptor.
JNJ-5207852 is extensively absorbed after oral administration and reaches high brain levels.
The data indicate that JNJ-5207852 is a novel, potent and selective H3 antagonist with good in vitro and in vivo efficacy, and confirm the wake-promoting effects of H3 receptor antagonists.
British Journal of Pharmacology (2004) 143, 649–661. doi:10.1038/sj.bjp.0705964
Two new series of 4-(1-alkyl-piperidin-4-yloxy)-benzonitriles and 4-(1-isopropyl-piperidin-4-yloxy)-benzylamines have been prepared. In vitro activity was determined at the recombinant human H(3) receptor and several members of these new series were found to be potent H(3) antagonists. The present compounds contain a 4-phenoxypiperidine core, which behaves as a conformationally restricted version of the 3-amino-1-propanol moiety common to the many previously described non-imidazole histamine H(3) ligands. One selected member of the new series, 4-[4-(1-isopropyl-piperidin-4-yloxy)-benzyl]-morpholine (13g), was found to be a potent, highly selective H(3) receptor antagonist with in vivo efficacy in a rat EEG model of wakefulness at doses as low as 1 mg/kg sc.
The synthesis and biological evaluation of novel tetrahydroisoquinoline, tetrahydroquinoline, and tetrahydroazepine antagonists of the human and rat H(3) receptors are described. The substitution around these rings as well as the nature of the substituent on nitrogen is explored. Several compounds with high affinity and selectivity for the human and rat H(3) receptors are reported.
Following the cloning of the histamine H3 receptor cDNA, the level of activity amongst both academic and pharmaceutical company laboratories has increased enormously. This activity has provided a greater understanding of the basic biology of the target, answering many questions about the potential therapeutic roles for histamine H3 receptor ligands and also raising some more fundamental questions about the nature of the receptor system. At the same time, the medicinal chemistry of the various ligands has also changed, primarily owing to the involvement of several pharmaceutical companies who have exploited high-throughput screening techniques to find novel templates for drug design. One consequence of these efforts is the discovery of numerous non-imidazole H3 antagonists, capable of addressing the shortcomings of the earlier imidazole-based compounds. Several of the newer structures appear to have acceptable drug-like properties with several advancing into the clinic and thus, the role of these agents as therapeutics should soon be established.
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