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Devin M Swanson,
Victoria D Wong,
Jill A Jablonowski,
Chandra Shah,
Dale A Rudolph,
Curt A Dvorak,
Mark Seierstad,
Lisa K Dvorak,
Kirsten Morton,
Diane Nepomuceno,
John R Atack,
Pascal Bonaventure,
Timothy W Lovenberg, Nicholas I Carruthers
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ABSTRACT: A series of small molecules based on a chemotype identified from our compound collection were synthesized and tested for binding affinity (IC(50)) at the human Neuropeptide Y Y(2) receptor (NPY Y(2)). Six of the 23 analogs tested possessed an NPY Y(2) IC(50) ≤ 15 nM. One member of this series, JNJ 31020028, is a selective, high affinity, receptor antagonist existing as a racemic mixture. As such a synthetic route to the desired enantiomer was designed starting from commercially available (S)-(+)-mandelic acid.
Bioorganic & medicinal chemistry letters 09/2011; 21(18):5552-6. · 2.65 Impact Factor
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ABSTRACT: The synthesis and SAR for a novel series of tetrahydropyrido[3,2-c]pyrroles is described. Optimization of the pendant aryl ring lead to high binding affinity at the 5-HT(7) receptor when small lipophilic groups were placed in the para position. Modification of the N-benzyl group and secondary amine were not well tolerated. A representative set of compounds was shown to be functional antagonists of the 5-HT(7) receptor.
Bioorganic & medicinal chemistry letters 01/2011; 21(1):42-4. · 2.65 Impact Factor
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James R Shoblock,
Natalie Welty,
Leah Aluisio,
Ian Fraser,
S Timothy Motley,
Kirsten Morton,
James Palmer,
Pascal Bonaventure, Nicholas I Carruthers,
Timothy W Lovenberg,
Jamin Boggs,
Ruggero Galici
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ABSTRACT: Orexin-1 receptor antagonists have been shown to block the reinforcing effects of drugs of abuse and food. However, whether blockade of orexin-2 receptor has similar effects has not been determined. We have recently described the in vitro and in vivo effects of JNJ-10397049, a selective and brain penetrant orexin-2 receptor antagonist.
The goal of these studies was to evaluate whether systemic administration of JNJ-10397049 blocks the rewarding effects of ethanol and reverses ethanol withdrawal in rodents. As a comparison, SB-408124, a selective orexin-1 receptor antagonist, was also evaluated.
Rats were trained to orally self-administer ethanol (8% v/v) or saccharin (0.1% v/v) under a fixed-ratio 3 schedule of reinforcement. A separate group of rats received a liquid diet of ethanol (8% v/v) and withdrawal signs were evaluated 4 h after ethanol discontinuation. In addition, ethanol-induced increases in extracellular dopamine levels in the nucleus accumbens were tested. In separate experiments, the acquisition, expression, and reinstatement of conditioned place preference (CPP) were evaluated in mice.
Our results indicate that JNJ-10397049 (1, 3, and 10 mg/kg, sc) dose-dependently reduced ethanol self-administration without changing saccharin self-administration, dopamine levels, or withdrawal signs in rats. Treatment with JNJ-10397049 (10 mg/kg, sc) attenuated the acquisition, expression, and reinstatement of ethanol CPP and ethanol-induced hyperactivity in mice. Surprisingly, SB-408124 (3, 10 and 30 mg/kg, sc) did not have any effect in these procedures.
Collectively, these results indicate, for the first time, that blockade of orexin-2 receptors is effective in reducing the reinforcing effects of ethanol.
Psychopharmacologia 12/2010; 215(1):191-203. · 4.08 Impact Factor
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Alejandro Santillan,
Kelly J McClure,
Brett D Allison,
Brian Lord,
Jamin D Boggs,
Kirsten L Morton,
Anita M Everson,
Diane Nepomuceno,
Michael A Letavic,
Alice Lee-Dutra,
Timothy W Lovenberg, Nicholas I Carruthers,
Cheryl A Grice
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ABSTRACT: Previous research on histamine H(3) antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH(3) affinities. Select analogs were profiled in a rat pharmacokinetic model.
Bioorganic & medicinal chemistry letters 11/2010; 20(21):6226-30. · 2.65 Impact Factor
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Ruggero Galici,
Amir H Rezvani,
Leah Aluisio,
Brian Lord,
Edward D Levin,
Ian Fraser,
Jamin Boggs,
Natalie Welty,
James R Shoblock,
S Timothy Motley,
Michael A Letavic, Nicholas I Carruthers,
Christine Dugovic,
Timothy W Lovenberg,
Pascal Bonaventure
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ABSTRACT: A few recent studies suggest that brain histamine levels and signaling via H(3) receptors play an important role in modulation of alcohol stimulation and reward in rodents.
The present study characterized the effects of a novel, selective, and brain penetrant H(3) receptor antagonist (JNJ-39220675) on the reinforcing effects of alcohol in rats.
The effect of JNJ-39220675 on alcohol intake and alcohol relapse-like behavior was evaluated in selectively bred alcohol-preferring (P) rats using the standard two-bottle choice method. The compound was also tested on operant alcohol self administration in non-dependent rats and on alcohol-induced ataxia using the rotarod apparatus. In addition, alcohol-induced dopamine release in the nucleus accumbens was tested in freely moving rats.
Subcutaneous administration of the selective H(3) receptor antagonist dose-dependently reduced both alcohol intake and preference in alcohol-preferring rats. JNJ-39220675 also reduced alcohol preference in the same strain of rats following a 3-day alcohol deprivation. The compound significantly and dose-dependently reduced alcohol self-administration without changing saccharin self-administration in alcohol non-dependent rats. Furthermore, the compound did not change the ataxic effects of alcohol, alcohol elimination rate, nor alcohol-induced dopamine release in nucleus accumbens.
These results indicate that blockade of H(3) receptor should be considered as a new attractive mechanism for the treatment of alcoholism.
Psychopharmacologia 11/2010; 214(4):829-41. · 4.08 Impact Factor
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Michael A Letavic,
Leah Aluisio,
John R Atack,
Pascal Bonaventure, Nicholas I Carruthers,
Christine Dugovic,
Anita Everson,
Mark A Feinstein,
Ian C Fraser,
Kenway Hoey, [......],
Brian Lord,
Timothy W Lovenberg,
Kiev S Ly,
Kirsten L Morton,
S Timothy Motley,
Diane Nepomuceno,
Michele Rizzolio,
Raymond Rynberg,
Kia Sepassi,
Jonathan Shelton
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ABSTRACT: The pre-clinical characterization of novel aryloxypyridine amides that are histamine H(3) receptor antagonists is described. These compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain. Several compounds were extensively profiled pre-clinically leading to the identification of two compounds suitable for nomination as development candidates.
Bioorganic & medicinal chemistry letters 07/2010; 20(14):4210-4. · 2.65 Impact Factor
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ABSTRACT: We have recently completed the synthesis of 1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, a hydroxyproline-based H(3) receptor antagonist, on 100 g scale. The synthesis proceeds through four steps and route selection was driven by a desire to minimize the cost-of-goods. Naturally occurring trans-4-hydroxy-L-proline was chosen as the precursor to the target's core, which necessitated an inversion at both stereogenic centers. The inversions were accomplished through strategic employment of La Rosa's lactone and a late-stage Mitsunobu reaction. A first generation synthesis that employed N-Boc-homopiperazine was improved in a second generation approach wherein homopiperazine was directly desymmetrized. Finally, the water solubility of a key intermediate necessitated the development of a nonextractive workup for the sodium triacetoxyborohydride reduction.
The Journal of Organic Chemistry 07/2010; 75(13):4463-71. · 4.45 Impact Factor
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Emily M Stocking,
Leah Aluisio,
John R Atack,
Pascal Bonaventure, Nicholas I Carruthers,
Christine Dugovic,
Anita Everson,
Ian Fraser,
Xiaohui Jiang,
Perry Leung,
Brian Lord,
Kiev S Ly,
Kirsten L Morton,
Diane Nepomuceno,
Chandravadan R Shah,
Jonathan Shelton,
Akinola Soyode-Johnson,
Michael A Letavic
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ABSTRACT: Pre-clinical characterization of novel substituted pyrrolidines that are high affinity histamine H(3) receptor antagonists is described. These compounds efficiently penetrate the CNS and occupy the histamine H(3) receptor in rat brain following oral administration. One compound, (2S,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, was extensively profiled and shows promise as a potential clinical candidate.
Bioorganic & medicinal chemistry letters 03/2010; 20(9):2755-60. · 2.65 Impact Factor
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ABSTRACT: 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.
Current topics in medicinal chemistry 02/2010; 10(5):596-616. · 4.47 Impact Factor
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Devin M Swanson,
Chandra R Shah,
Brian Lord,
Kirsten Morton,
Lisa K Dvorak,
Curt Mazur,
Richard Apodaca,
Wei Xiao,
Jamin D Boggs,
Mark Feinstein,
Sandy J Wilson,
Ann J Barbier,
Pascal Bonaventure,
Timothy W Lovenberg, Nicholas I Carruthers
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ABSTRACT: A series of small molecules consisting of a heterocyclic core flanked by two basic functionalities were synthesized and screened for in vitro affinity at the human histamine H(3) receptor (hH(3)R). Nine of the twenty-eight compounds tested were found to possess a hH(3)R K(i) of less than 5 nM and consisted of a diverse range of central hetero-aromatic linkers (pyridine, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, and pyrrole). One member of this series, (4-isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanone (37), was found to be a high affinity, selective antagonist that crosses the blood-brain barrier and occupies H(3) receptors after oral administration in the rat.
European journal of medicinal chemistry 07/2009; 44(11):4413-25. · 3.27 Impact Factor
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Curt A Dvorak,
Richard Apodaca,
Wei Xiao,
Jill A Jablonowski,
Pascal Bonaventure,
Christine Dugovic,
Jonathan Shelton,
Brian Lord,
Kirsten Miller,
Lisa K Dvorak,
Timothy W Lovenberg, Nicholas I Carruthers
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ABSTRACT: A series of (4-aminobutyn-1-yl)benzylamines were prepared and the SAR around three key areas: (1) the amine attached to the butynyl linker (R(3)R(4)N-); (2) the benzylamine moiety (R(1)R(2)N-); and (3) the point of attachment of the benzylamine group (R(1)R(2)N- in the ortho, meta, or para positions) was examined. One compound, 4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine (9s) was chosen for further profiling and found to be a selective histamine H(3) antagonist with desirable drug-like properties. Ex vivo receptor occupancy studies established that 9s does occupy H(3) binding sites in the brain of rats after oral administration. Subcutaneous doses of 9s (10mg/kg) given during the natural sleep phase demonstrated robust wake-promoting effects.
European journal of medicinal chemistry 06/2009; 44(10):4098-106. · 3.27 Impact Factor
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Christine Dugovic,
Jonathan E Shelton,
Leah E Aluisio,
Ian C Fraser,
Xiaohui Jiang,
Steven W Sutton,
Pascal Bonaventure,
Sujin Yun,
Xiaorong Li,
Brian Lord,
Curt A Dvorak, Nicholas I Carruthers,
Timothy W Lovenberg
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ABSTRACT: Orexins are peptides produced by lateral hypothalamic neurons that exert a prominent role in the maintenance of wakefulness by activating orexin-1 (OX1R) and orexin-2 (OX2R) receptor located in wake-active structures. Pharmacological blockade of both receptors by the dual OX1/2R antagonist (2R)-2-[(1S)-6,7-dimethoxy-1-{2-[4-(trifluoromethyl)phenyl]ethyl}-3,4-dihydroisoquinolin-2(1H)-yl]-N-methyl-2-phenylethanamide (almorexant) has been shown to promote sleep in animals and humans during their active period. However, the selective distribution of OX1R and OX2R in distinct neuronal circuits may result in a differential impact of these receptors in sleep-wake modulation. The respective role of OX1R and OX2R on sleep in correlation with monoamine release was evaluated in rats treated with selective antagonists alone or in combination. When administered in either phase of the light/dark cycle, the OX2R antagonist 1-(2,4-dibromophenyl)-3-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl]urea (JNJ-10397049) decreased the latency for persistent sleep and increased nonrapid eye movement and rapid eye movement sleep time. Almorexant produced less hypnotic activity, whereas the OX1R antagonist 1-(6,8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino)phenyl]urea (SB-408124) had no effect. Microdialysis studies showed that either OX2R or OX1/2R antagonism decreased extracellular histamine concentration in the lateral hypothalamus, whereas both OX1R and OX1/2R antagonists increased dopamine release in the prefrontal cortex. Finally, coadministration of the OX1R with the OX2R antagonist greatly attenuated the sleep-promoting effects of the OX2R antagonist. These results indicate that blockade of OX2R is sufficient to initiate and prolong sleep, consistent with the hypothesis of a deactivation of the histaminergic system. In addition, it is suggested that simultaneous inhibition of OX1R attenuates the sleep-promoting effects mediated by selective OX2R blockade, possibly correlated with dopaminergic neurotransmission.
Journal of Pharmacology and Experimental Therapeutics 05/2009; 330(1):142-51. · 3.83 Impact Factor
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Jill A Jablonowski,
Kiev S Ly,
Michael Bogenstaetter,
Curt A Dvorak,
Jamin D Boggs,
Lisa K Dvorak,
Brian Lord,
Kirsten L Miller,
Curt Mazur,
Sandy J Wilson,
Timothy W Lovenberg, Nicholas I Carruthers
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ABSTRACT: A novel series of imidazole containing histamine H(3) receptor ligands were investigated and found to be potent functional antagonists. After improving the stability of these molecules towards liver microsomes, these compounds were found to have no appreciable affinity for CYP P450s. Subsequent in vivo experiments showed significant brain uptake of (4-chloro-phenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone 22.
Bioorganic & medicinal chemistry letters 01/2009; 19(3):903-7. · 2.65 Impact Factor
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Michael A Letavic,
John M Keith,
Kiev S Ly,
Pascal Bonaventure,
Mark A Feinstein,
Brian Lord,
Kirsten L Miller,
S Timothy Motley,
Diane Nepomuceno,
Steven W Sutton, Nicholas I Carruthers
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ABSTRACT: The synthesis and biological activity of a new series of 2-aryloxymethylmorpholine histamine H(3) antagonists is described. The new compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain.
Bioorganic & medicinal chemistry letters 10/2008; 18(21):5796-9. · 2.65 Impact Factor
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Leah Aluisio,
Brian Lord,
Ann J Barbier,
Ian C Fraser,
Sandy J Wilson,
Jamin Boggs,
Lisa K Dvorak,
Michael A Letavic,
Bruce E Maryanoff, Nicholas I Carruthers,
Pascal Bonaventure,
Timothy W Lovenberg
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ABSTRACT: Triple reuptake inhibitors, which block the serotonin transporter (SERT), norepinephrine transporter (NET) and dopamine transporter (DAT) in the central nervous system have been described as therapeutic alternatives for classical selective serotonin reuptake inhibitors, with advantages due to their multiple mechanisms of action. JNJ-7925476 (trans-6-(4-ethynylphenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline) is a selective and potent inhibitor of the SERT, NET, and DAT (K(i)=0.9, 17 and 5.2 nM, respectively). Following subcutaneous dosing in rat, JNJ-7925476 was rapidly absorbed into the plasma, and drug concentrations in the brain tracked with those in the plasma but were 7-fold higher. The ED(50) values for JNJ-7925476 occupancy of the SERT, NET, and DAT in rat brain were 0.18, 0.09 and 2.4 mg/kg, respectively. JNJ-7925476 (0.1-10 mg/kg, s.c.) rapidly induced a robust, dose-dependent increase in extracellular serotonin, dopamine, and norepinephrine levels in rat cerebral cortex. The compound also showed potent antidepressant-like activity in the mouse tail suspension test (ED(50)=0.3 mg/kg, i.p.). These results demonstrate that JNJ-7925476 is a triple reuptake inhibitor with in-vivo efficacy in biochemical and behavioral models of depression.
European Journal of Pharmacology 07/2008; 587(1-3):141-6. · 2.52 Impact Factor
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ABSTRACT: Currently, the only clinically effective treatment for Alzheimer's disease (AD) is the use of acetylcholinesterase (AChE) inhibitors. These inhibitors have limited efficacy in that they only treat the symptoms and not the disease itself. Additionally, they often have unpleasant side effects. Here we consider the viability of a single molecule having the actions of both an AChE inhibitor and histamine H(3) receptor antagonist. Both histamine H(3) receptor antagonists and AChE inhibitors improve and augment cholinergic neurotransmission in the cortex. However, whereas an AChE inhibitor will impart its effect everywhere, a histamine H(3) antagonist will raise acetylcholine levels mostly in the brain as its mode of action will primarily be on the central nervous system. Therefore, the combination of both activities in a single molecule could be advantageous. Indeed, studies suggest an appropriate dual-acting compound may offer the desired therapeutic effect with fewer unpleasant side effects [CNS Drugs2004, 18, 827]. Further, recent studies(2) indicate the peripheral anionic site (PAS) of AChE interacts with the beta-amyloid (betaA) peptide. Consequently, a molecule capable of disrupting this interaction may have a significant impact on the production of or the aggregation of betaA. This may result in slowing down the progression of the disease rather than only treating the symptoms as current therapies do. Here, we detail how the use of the available crystal structure information, pharmacophore modeling and docking (automated, manual, classical, and QM/MM) lead to the identification of an AChE inhibitor-histamine H(3) receptor antagonist. Further, based on our models we speculate that this dual-acting compound may interact with the PAS. Such a dual-acting compound may be able to affect the pathology of AD in addition to providing symptomatic relief.
Bioorganic & medicinal chemistry 04/2008; 16(6):2968-73. · 2.82 Impact Factor
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ABSTRACT: The synthesis and SAR for a novel series of 2-alkyl-4-aryl-tetrahydro-pyrido-pyrimidines and 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines is described. Representative compounds were shown to be subtype selective 5-HT(2A) antagonists. Optimal placement of a basic nitrogen relative to the pyrimidine and the presence of a 4-fluorophenyl group in the pyrimidine 4-position was found to have a profound effect on affinity and selectivity.
Bioorganic & medicinal chemistry letters 04/2008; 18(6):2103-8. · 2.65 Impact Factor
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Kiev S Ly,
Michael A Letavic,
John M Keith,
Jennifer M Miller,
Emily M Stocking,
Ann J Barbier,
Pascal Bonaventure,
Brian Lord,
Xiaohui Jiang,
Jamin D Boggs,
Lisa Dvorak,
Kirsten L Miller,
Diane Nepomuceno,
Sandy J Wilson, Nicholas I Carruthers
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ABSTRACT: 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.
Bioorganic & medicinal chemistry letters 02/2008; 18(1):39-43. · 2.65 Impact Factor
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Ann J Barbier,
Leah Aluisio,
Brian Lord,
Ying Qu,
Sandy J Wilson,
Jamin D Boggs,
Pascal Bonaventure,
Kirsten Miller,
Ian Fraser,
Lisa Dvorak,
Cindy Pudiak,
Christine Dugovic,
Jonathan Shelton,
Curt Mazur,
Michael A Letavic, Nicholas I Carruthers,
Timothy W Lovenberg
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ABSTRACT: 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.
European Journal of Pharmacology 01/2008; 576(1-3):43-54. · 2.52 Impact Factor
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ABSTRACT: 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.
Bioorganic & Medicinal Chemistry Letters 11/2007; 17(19):5325-9. · 2.55 Impact Factor
