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ABSTRACT: Molecular details of µ opioid receptor activations were obtained using molecular dynamics simulations of the receptor in the presence of 3 agonists, 3 antagonists, a partial agonist and on the constitutively active T279K mutant. Agonists have a higher probability of direct interactions of their basic nitrogen (N) with Asp147 as compared to antagonists, indicating that direct ligand-Asp147 interactions modulate activation. Medium size substituents on the basic N of antagonists lead to steric interactions that perturb N-Asp147 interactions, while additional favorable interactions occur with larger basic N substituents, such as in N-phenethylnormorphine, restoring N-Asp147 interactions, leading to agonism. With the orvinols, the increased size of the C19 substituent in buprenorphine over diprenorphine leads increased interactions with residues adjacent to Asp147, partially overcoming the presence of the cyclopropyl N substituent, such that buprenorphine is a partial agonist. Results also indicate different conformational properties of the intracellular regions of the transmembrane helices in agonists versus antagonists.
The Journal of Physical Chemistry B 06/2013; · 3.70 Impact Factor
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ABSTRACT: Opioid narcotics are used for the treatment of moderate-to-severe pain and primarily exert their analgesic effects through µ receptors. Although, traditional µ agonists can cause undesired side effects, including tolerance, addition of δ antagonists can attenuate said side effects. Herein, we report 4a,9-dihydroxy-7a-(hydroxymethyl)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (UMB 425) a 5,14-bridged morphinan-based orvinol precursor synthesized from thebaine. Although UMB 425 lacks δ-specific motifs, conformationally sampled pharmacophore models for µ and δ receptors predict it to have efficacy similar to morphine at µ receptors and similar to naltrexone at δ receptors, due to the compound sampling conformations in which the hydroxyl moiety interacts with the receptors similar to orvinols. As predicted, UMB 425 exhibits a mixed µ agonist/δ antagonist profile as determined in receptor binding and [35S]GTPγS functional assays in CHO cells. In vivo studies in mice show that UMB 425 displays potent antinociception in the hot plate and tail-flick assays. The antinociceptive effects of UMB 425 are blocked by naloxone, but not by the κ-selective antagonist norbinaltorphimine. During a six-day tolerance paradigm, UMB 425 maintains significantly greater antinociception compared to morphine. These studies thus indicate that even in the absence of δ-specific motifs fused to the C-ring, UMB 425 has mixed µ agonist/δ antagonist properties in vitro that translate to reduced tolerance liabilities in vivo.
ACS Chemical Neuroscience 05/2013; · 3.68 Impact Factor
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Laura E McKnight,
E Prabhu Raman,
Padmavani Bezawada,
Sucheta Kudrimoti,
Paul T Wilder,
Kira G Hartman,
Raquel Godoy-Ruiz,
Eric A Toth, Andrew Coop,
Alexander D Mackerell,
David J Weber
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ABSTRACT: Background: Methamphetamine (METH) causes hyperthermia and dopaminergic neurotoxicity in the rodent striatum. METH interacts with σ receptors and σ receptor antagonists normally mitigate METH-induced hyperthermia and dopaminergic neurotoxicity. The present study was undertaken because in two experiments, pretreatment with σ receptor antagonists failed to attenuate METH-induced hyperthermia in mice. This allowed us to determine whether the ability of σ receptor antagonists (AZ66 and AC927) to mitigate METH-induced neurotoxicity depends upon their ability to modulate METH-induced hyperthermia. Methods: Mice were treated using a repeated dosing paradigm and body temperatures recorded. Striatal dopamine was measured one week post-treatment. Results: The data indicate that the ability of σ receptor antagonists to attenuate METH-induced dopaminergic neurotoxicity is linked to their ability to block METH-induced hyperthermia. Conclusion: The ability of σ receptor antagonists to mitigate METH-induced hyperthermia may contribute to its neuroprotective actions.
Pharmacological reports: PR 01/2013; 65(2):343-9. · 2.44 Impact Factor
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Laura E McKnight,
E Prabhu Raman,
Padmavani Bezawada,
Sucheta Kudrimoti,
Paul T Wilder,
Kira G Hartman,
Raquel Godoy-Ruiz,
Eric A Toth, Andrew Coop,
Alexander D Mackerell,
David J Weber
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ABSTRACT: Molecular Dynamics simulations of the pentamidine-S100B complex, where two molecules of pentamidine bind per monomer of S100B, were performed in an effort to determine what properties would be desirable in a pentamidine-derived compound as an inhibitor for S100B. These simulations predicted that increasing the linker length of the compound would allow a single molecule to span both pentamidine binding sites on the protein. The resulting compound, SBi4211 (also known as heptamidine), was synthesized and experiments to study its inhibition of S100B were performed. The 1.65 Å X-ray crystal structure was determined for Ca(2+)-S100B-heptamdine and gives high-resolution information about key contacts that facilitate the interaction between heptamidine and S100B. Additionally, NMR HSQC experiments with both compounds show that heptamidine interacts with the same region of S100B as pentamidine. Heptamidine is able to selectively kill melanoma cells with S100B over those without S100B, indicating that its binding to S100B has an inhibitory effect and that this compound may be useful in designing higher-affinity S100B inhibitors as a treatment for melanoma and other S100B-related cancers.
ACS Medicinal Chemistry Letters 12/2012; 3(12):975-979. · 3.36 Impact Factor
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ABSTRACT: Morphinans have a storied history in medicinal chemistry as pain management drugs but have received attention as modulators of cholinergic signaling for the treatment of Alzheimer's Disease (AD). Galantamine is a reversible, competitive acetylcholinesterase (AChE) inhibitor and allosteric potentiating ligand of nicotinic acetylcholine receptors (nAChR-APL) that shares many common structural elements with morphinan-based opioids. The structurally diverse opioids codeine and eseroline, like galantamine, are also nAChR-APL that have greatly diminished affinity for AChE, representing potential lead compounds for selective nAChR-APL development. In accordance with the emerging repurposing trend of evaluating known compounds for novel pharmacological activity, ongoing research on augmentation of cholinergic signaling that has been aided by the use of opioids will be reviewed.
Mini Reviews in Medicinal Chemistry 08/2012; · 2.53 Impact Factor
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ABSTRACT: A series of phenylpropyloxyethylamines and cinnamyloxyethylamines were synthesized as deconstructed analogs of 14-phenylpropyloxymetopon and analyzed for opioid receptor binding affinity. Using the Conformationally Sampled Pharmacophore modeling approach, we discovered a series of compounds lacking a tyrosine mimetic, historically considered essential for μ opioid binding. Based on the binding studies, we have identified the optimal analogs to be N-methyl-N-phenylpropyl-2-(3-phenylpropoxy)ethanamine, with 1520 nM, and 2-(cinnamyloxy)-N-methyl-N-phenethylethanamine with 1680 nM affinity for the μ opioid receptor. These partial opioid structure analogs will serve as the novel lead compounds for future optimization studies.
Bioorganic & medicinal chemistry 05/2012; 20(14):4556-63. · 2.82 Impact Factor
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ABSTRACT: Methamphetamine is a highly addictive psychostimulant drug of abuse that causes neurotoxicity with high or repeated dosing. Earlier studies demonstrated the ability of the selective σ receptor ligand N-phenethylpiperidine oxalate (AC927) to attenuate the neurotoxic effects of methamphetamine in vivo. However, the precise mechanisms through which AC927 conveys its protective effects remain to be determined. With the use of differentiated NG108-15 cells as a model system, the effects of methamphetamine on neurotoxic endpoints and mediators such as apoptosis, necrosis, generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and dopamine release were examined in the absence and presence of AC927. Methamphetamine at physiologically relevant micromolar concentrations caused apoptosis in NG108-15 cells. At higher concentrations of methamphetamine, necrotic cell death was observed. At earlier time points, methamphetamine caused ROS/RNS generation, which was detected with the fluorigenic substrate 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescin diacetate, acetyl ester, in a concentration- and time-dependent manner. N-Acetylcysteine, catalase, and l-N(G)-monomethyl arginine citrate inhibited the ROS/RNS fluorescence signal induced by methamphetamine, which suggests the formation of hydrogen peroxide and RNS. Exposure to methamphetamine also stimulated the release of dopamine from NG108-15 cells into the culture medium. AC927 attenuated methamphetamine-induced apoptosis, necrosis, ROS/RNS generation, and dopamine release in NG108-15 cells. Together, the data suggest that modulation of σ receptors can mitigate methamphetamine-induced cytotoxicity, ROS/RNS generation, and dopamine release in cultured cells.
Molecular pharmacology 11/2011; 81(3):299-308. · 4.53 Impact Factor
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ABSTRACT: The 14-position of natural opiates (e.g. morphine) are unsubstituted, however synthetic approaches have uncovered that functionalizing position 14 gives rise to a wide range of diverse activities. This review focuses on SAR of the position, with the aim of aiding in the search for opioid analgesics with improved clinical profiles.
Mini Reviews in Medicinal Chemistry 08/2011; 11(12):1002-8. · 2.53 Impact Factor
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ABSTRACT: Despite being studied for over 30 years, a consensus structure-activity relationship (SAR) that encompasses the full range peptidic and nonpeptidic μ-opioid receptor ligands is still not available. To achieve a consensus SAR the Conformationally Sampled Pharmacophore (CSP) method was applied to develop a predictive model of the efficacy of μ-opioid receptor ligands. Emphasis was placed on predicting the efficacy of a wide range of agonists, partial agonists, and antagonists as well as understanding their mode of interaction with the receptor. Inclusion of all accessible conformations of each ligand, a central feature of the CSP method, enabled structural features between diverse μ-opioid receptor ligands that dictate efficacy to be identified. The models were validated against a diverse collection of peptidic and nonpeptidic ligands, including benzomorphans, fentanyl (4-anilinopiperidine), methadone (3,3-diphenylpropylamines), etonitazene (benzimidazole derivatives), funaltrexamine (C6-substituted 4,5-epoxymorphinan), and herkinorin. The model predicts (1) that interactions of ligands with the B site, as with the 19-alkyl substituents of oripavines, modulate the extent of agonism; (2) that agonists with long N-substituents, as with fentanyl and N-phenethylnormorphine, can bind in an orientation such that the N substitutent interacts with the B site that also allows the basic N-receptor Asp interaction essential for agonism; and (3) that the μ agonist herkinorin, that lacks a basic nitrogen, binds to the receptor in a manner similar to the traditional opioids via interactions mediated by water or a ion. Importantly, the proposed CSP model can be reconciled with previously published SAR models for the μ receptor.
The Journal of Physical Chemistry B 06/2011; 115(22):7487-96. · 3.70 Impact Factor
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ABSTRACT: In the absence of three-dimensional (3D) structures of potential drug targets, ligand-based drug design is one of the popular approaches for drug discovery and lead optimization. 3D structure-activity relationships (3D QSAR) and pharmacophore modeling are the most important and widely used tools in ligand-based drug design that can provide crucial insights into the nature of the interactions between drug target and ligand molecule and provide predictive models suitable for lead compound optimization. This review article will briefly discuss the features and potential application of recent advances in ligand-based drug design, with emphasis on a detailed description of a novel 3D QSAR method based on the conformationally sample pharmacophore (CSP) approach (denoted CSP-SAR). In addition, data from a published study are used to compare the CSP-SAR approach to the Catalyst method, emphasizing the utility of the CSP approach for ligand-based model development.
Current Computer - Aided Drug Design 03/2011; 7(1):10-22. · 1.76 Impact Factor
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ABSTRACT: Methamphetamine interacts with sigma (σ) receptors and AC927, a selective σ receptor ligand, protects against methamphetamine-induced dopaminergic neurotoxicity. In the present study, the effects of AC927 on methamphetamine-induced hyperthermia and striatal serotonergic neurotoxicity were evaluated. Male, Swiss Webster mice were injected (i.p.) every 2 h, for a total of four times, with one of the following treatments: Saline+Saline; Saline+Methamphetamine (5 mg/kg); AC927 (5, 10, 20 mg/kg)+Methamphetamine (5 mg/kg); or AC927 (5, 10, 20 mg/kg)+Saline. Pretreatment with AC927 (10 mg/kg) significantly attenuated methamphetamine-induced striatal serotonin depletions, striatal serotonin transporter reductions, and hyperthermia. At the doses tested, AC927 itself had no significant effects on serotonin levels, serotonin transporter expression, or body temperature. To evaluate the effects of higher ambient temperature on methamphetamine-induced neurotoxicity, groups of mice were treated at 37 °C. Overall, there was an inverse correlation between the body temperature of the animals and striatal serotonin levels. Together, the data suggest that AC927 (10 mg/kg) protects against methamphetamine-induced neurotoxicity. The reduction of methamphetamine-induced hyperthermia by AC927 may contribute to the observed neuroprotection in vivo.
Pharmacology Biochemistry and Behavior 03/2011; 98(1):12-20. · 2.53 Impact Factor
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ABSTRACT: Sigma receptors represent a unique structural class of proteins and they have become increasingly studied as viable medication development targets for neurological and psychiatric disorders, including drug abuse. Earlier studies have shown that cocaine and many other abused substances interact with sigma receptors and that antagonism of these proteins can mitigate their actions.
In the present study, AC927 (1-(2-phenethyl)piperidine oxalate), a selective sigma receptor ligand, was tested against the behavioral and toxic effects of cocaine in laboratory animals.
Acute administration of AC927 in male, Swiss Webster mice significantly attenuated cocaine-induced convulsions, lethality, and locomotor activity, at doses that alone had no significant effects on behavior. Subchronic administration of AC927 also attenuated cocaine-induced conditioned place preference in mice, at doses that alone had no effects on place conditioning. In drug discrimination studies in male, Sprague-Dawley rats, AC927 partially substituted for the discriminative stimulus effects of cocaine. When it was administered with cocaine, AC927 shifted the cocaine dose-response curve to the left, suggesting an enhancement of the discriminative stimulus effects of cocaine. In non-human primates, AC927 was self-administered, maintaining responding that was intermediate between contingent saline and a maintenance dose of cocaine.
The ability of AC927 to elicit some cocaine-like appetitive properties and to also reduce many cocaine-induced behaviors suggests that it is a promising lead for the development of a medication to treat cocaine abuse.
Drug and alcohol dependence 03/2011; 118(1):40-7. · 3.60 Impact Factor
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ABSTRACT: Chronic clinical pain remains poorly treated. Despite attempts to develop novel analgesic agents, opioids remain the standard analgesics of choice in the clinical management of chronic and severe pain. However, mu opioid analgesics have undesired side effects including, but not limited to, respiratory depression, physical dependence and tolerance. A growing body of evidence suggests that P-glycoprotein (P-gp), an efflux transporter, may contribute a systems-level approach to the development of opioid tolerance. Herein, we describe current in vitro and in vivo methodology available to analyze interactions between opioids and P-gp and critically analyze P-gp data associated with six commonly used mu opioids to include morphine, methadone, loperamide, meperidine, oxycodone, and fentanyl. Recent studies focused on the development of opioids lacking P-gp substrate activity are explored, concentrating on structure-activity relationships to develop an optimal opioid analgesic lacking this systems-level contribution to tolerance development. Continued work in this area will potentially allow for delineation of the mechanism responsible for opioid-related P-gp up-regulation and provide further support for evidence based medicine supporting clinical opioid rotation.
Current topics in medicinal chemistry 11/2010; 11(9):1157-64. · 4.47 Impact Factor
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ABSTRACT: S100B is highly over-expressed in many cancers, including malignant melanoma. In such cancers, S100B binds wild-type p53 in a calcium-dependent manner, sequestering it, and promoting its degradation, resulting in the loss of p53-dependent tumor suppression activities. Therefore, S100B inhibitors may be able to restore wild-type p53 levels in certain cancers and provide a useful therapeutic strategy. In this regard, an automated and sensitive fluorescence polarization competition assay (FPCA) was developed and optimized to screen rapidly for lead compounds that bind Ca(2+)-loaded S100B and inhibit S100B target complex formation. A screen of 2000 compounds led to the identification of 26 putative S100B low molecular weight inhibitors. The binding of these small molecules to S100B was confirmed by nuclear magnetic resonance spectroscopy, and additional structural information was provided by x-ray crystal structures of several compounds in complexes with S100B. Notably, many of the identified inhibitors function by chemically modifying Cys84 in protein. These results validate the use of high-throughput FPCA to facilitate the identification of compounds that inhibit S100B. These lead compounds will be the subject of future optimization studies with the ultimate goal of developing a drug with therapeutic activity for the treatment of malignant melanoma and/or other cancers with elevated S100B.
International Journal of High Throughput Screening 07/2010; 2010(1):109-126.
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Leandro C Cerchietti,
Alexandru F Ghetu,
Xiao Zhu,
Gustavo F Da Silva,
Shijun Zhong,
Marilyn Matthews,
Karen L Bunting,
Jose M Polo,
Christophe Farès,
Cheryl H Arrowsmith,
Shao Ning Yang,
Monica Garcia, Andrew Coop,
Alexander D Mackerell,
Gilbert G Privé,
Ari Melnick
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ABSTRACT: The BCL6 transcriptional repressor is the most frequently involved oncogene in diffuse large B cell lymphoma (DLBCL). We combined computer-aided drug design with functional assays to identify low-molecular-weight compounds that bind to the corepressor binding groove of the BCL6 BTB domain. One such compound disrupted BCL6/corepressor complexes in vitro and in vivo, and was observed by X-ray crystallography and NMR to bind the critical site within the BTB groove. This compound could induce expression of BCL6 target genes and kill BCL6-positive DLBCL cell lines. In xenotransplantation experiments, the compound was nontoxic and potently suppressed DLBCL tumors in vivo. The compound also killed primary DLBCLs from human patients.
Cancer cell 04/2010; 17(4):400-11. · 25.29 Impact Factor
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ABSTRACT: A series of pyridylpiperazines was synthesized and analyzed for sigma receptor binding affinity to determine the optimal pyridyl nitrogen position and chain length for the sigma(1) and sigma(2) receptor recognition. The (3-pyridyl)piperazines and (4-pyridyl)piperazines favor sigma(1) receptors, while previously studied (2-pyridyl)piperazines favor sigma(2) receptors.
Bioorganic & medicinal chemistry letters 03/2010; 20(8):2564-5. · 2.65 Impact Factor
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ABSTRACT: The Diels - Alder reaction was applied to 4,5-epoxymorphinan opioids to generate a novel aromatic cycloadduct at C(7) - C(8): Thermolytic cleavage of sultine 8 produced the reactive diene o-quinodimethane 7 which condensed favorably with codeine (11), but not with codeinone (9) or 14- hydroxycodeinone (10), producing the desired tetrahydronaphtho adduct 12 with (7R,8R) geometry (Scheme). The configuration of the cycloadduct was determined by 1D- and 2D-NMR experiments. The unanticipated reactivity of these codeine derivatives was investigated by quantum-mechanical calculations, and it was determined that steric effects of the 6-keto and 14-hydroxy group likely precluded condensation by raising the molecular energy of their respective transition states.
Helvetica Chimica Acta 02/2010; 93(2):220-226. · 1.48 Impact Factor
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ABSTRACT: Although oxycodone is the most often used opioid agonist, it remains one of the most understudied drugs. We used microarray analysis to better understand the global changes in gene expression in brain tissues of rats repeatedly treated with oxycodone. Many genes were significantly regulated by oxycodone (e.g., Fkbp5, Per2, Rt1.Dα, Slc16a1, and Abcg2). Validation of the microarray data by quantitative real-time-polymerase chain reaction (Q-PCR) indicated that there was a strong significant correlation (r = 0.979, p < 0.0000001) between the Q-PCR and the microarray data. Using MetaCore (a computational platform), many biological processes were identified [e.g., organic anion transport (p = 7.251 × 10−4) and regulation of immune response (p = 5.090 × 10−4)]. Among the regulated genes, Abcg2 mRNA was up-regulated by 2.1-fold, which was further confirmed by immunoblotting (1.8-fold up-regulation). Testing the Abcg2 affinity status of oxycodone using an Abcg2 ATPase assay suggests that oxycodone behaves as an Abcg2 substrate only at higher concentrations (≥500 μM). Furthermore, brain uptake studies demonstrated that oxycodone-induced Abcg2 up-regulation resulted in a significant (p < 0.05) decrease (∼2-fold) in brain/plasma ratios of mitoxantrone. These results highlight markers/mediators of neuronal responses and identify regulatory pathways involved in the pharmacological action of oxycodone. These results also identify genes that potentially modulate tolerance, dependence, immune response, and drug-drug interactions. Finally, our findings suggest that oxycodone-induced up-regulation of Abcg2 enhanced the efflux of the Abcg2 substrate, mitoxantrone, limiting its brain accumulation and resulting in an undesirable drug-drug interaction. Extrapolating these results to other Abcg2 substrates (e.g., daunorubicin and doxorubicin) indicates that the brain uptake of these agents may be affected if they are administered concomitantly with oxycodone.
Drug metabolism and disposition: the biological fate of chemicals 09/2009; · 3.74 Impact Factor
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ABSTRACT: Structural studies are part of a rational drug design program aimed at inhibiting the S100B-p53 interaction and restoring wild-type p53 function in malignant melanoma. To this end, structures of three compounds (SBi132, SBi1279, and SBi523) bound to Ca(2+)-S100B were determined by X-ray crystallography at 2.10 A (R(free) = 0.257), 1.98 A (R(free) = 0.281), and 1.90 A (R(free) = 0.228) resolution, respectively. Upon comparison, SBi132, SBi279, and SBi523 were found to bind in distinct locations and orientations within the hydrophobic target binding pocket of Ca(2+)-S100B with minimal structural changes observed for the protein upon complex formation with each compound. Specifically, SBi132 binds nearby residues in loop 2 (His-42, Phe-43, and Leu-44) and helix 4 (Phe-76, Met-79, Ile-80, Ala-83, Cys-84, Phe-87, and Phe-88), whereas SBi523 interacts with a separate site defined by residues within loop 2 (Ser-41, His-42, Phe-43, Leu-44, Glu-45, and Glu-46) and one residue on helix 4 (Phe-87). The SBi279 binding site on Ca(2+)-S100B overlaps the SBi132 and SBi523 sites and contacts residues in both loop 2 (Ser-41, His-42, Phe-43, Leu-44, and Glu-45) and helix 4 (Ile-80, Ala-83, Cys-84, Phe-87, and Phe-88). NMR data, including saturation transfer difference (STD) and (15)N backbone and (13)C side chain chemical shift perturbations, were consistent with the X-ray crystal structures and demonstrated the relevance of all three small molecule-S100B complexes in solution. The discovery that SBi132, SBi279, and SBi523 bind to proximal sites on Ca(2+)-S100B could be useful for the development of a new class of molecule(s) that interacts with one or more of these binding sites simultaneously, thereby yielding novel tight binding inhibitors specific for blocking protein-protein interactions involving S100B.
Biochemistry 07/2009; 48(26):6202-12. · 3.42 Impact Factor
