Showing papers by "ACADIA Pharmaceuticals Inc. published in 2005"

Cholecystokinin in the Rostral Ventromedial Medulla Mediates Opioid-Induced Hyperalgesia and Antinociceptive Tolerance

Abstract: Opioid-induced hyperalgesia is characterized by hypersensitivity to innocuous or noxious stimuli during sustained opiate administration. Microinjection of lidocaine into the rostral ventromedial medulla (RVM), or dorsolateral funiculus (DLF) lesion, abolishes opioid-induced hyperalgesia, suggesting the importance of descending pain facilitation mechanisms. Here, we investigate the possibility that cholecystokinin (CCK), a pronociceptive peptide, may drive such descending facilitation from the RVM during continuous opioid administration. In opioid-naive rats, CCK in the RVM produced acute tactile and thermal hypersensitivity that was antagonized by the CCK 2 receptor antagonist L365,260 or by DLF lesion. CCK in the RVM also acutely displaced the spinal morphine antinociceptive dose-response curve to the right. Continuous systemic morphine elicited sustained tactile and thermal hypersensitivity within 3 d. Such hypersensitivity was reversed in a time-dependent manner by L365,260 in the RVM, and blockade of CCK 2 receptors in the RVM also blocked the rightward displacement of the spinal morphine antinociceptive dose-response curve. Microdialysis studies in rats receiving continuous morphine showed an approximately fivefold increase in the basal levels of CCK in the RVM when compared with controls. These data suggest that activation of CCK 2 receptors in the RVM promotes mechanical and thermal hypersensitivity and antinociceptive tolerance to morphine. Enhanced, endogenous CCK activity in the RVM during sustained morphine exposure may diminish spinal morphine antinociceptive potency by activating descending pain facilitatory mechanisms to exacerbate spinal nociceptive sensitivity. Prevention of opioid-dose escalation in chronic pain states by CCK receptor antagonism represents a potentially important strategy to limit unintended enhanced clinical pain and analgesic tolerance.

Intrinsic Efficacy of Antipsychotics at Human D2, D3, and D4 Dopamine Receptors: Identification of the Clozapine Metabolite N-Desmethylclozapine as a D2/D3 Partial Agonist

Abstract: Drugs that antagonize D2-like receptors are effective antipsychotics, but the debilitating movement disorder side effects associated with these drugs cannot be dissociated from dopamine receptor blockade. The "atypical" antipsychotics have a lower propensity to cause extrapyramidal symptoms (EPS), but the molecular basis for this is not fully understood nor is the impact of inverse agonism upon their clinical properties. Using a cell-based functional assay, we demonstrate that overexpression of Galphao induces constitutive activity in the human D2-like receptors (D2, D3, and D4). A large collection of typical and atypical antipsychotics was profiled for activity at these receptors. Virtually all were D2 and D3 inverse agonists, whereas none was D4 inverse agonist, although many were potent D4 antagonists. The inverse agonist activity of haloperidol at D2 and D3 receptors could be reversed by mesoridazine demonstrating that there were significant differences in the degrees of inverse agonism among the compounds tested. Aripiprazole and the principle active metabolite of clozapine NDMC [8-chloro-11-(1-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine] were identified as partial agonists at D2 and D3 receptors, although clozapine itself was an inverse agonist at these receptors. NDMC-induced functional responses could be reversed by clozapine. It is proposed that the low incidence of EPS associated with clozapine and aripiprazole used may be due, in part, to these partial agonist properties of NDMC and aripiprazole and that bypassing clozapine blockade through direct administration of NDMC to patients may provide superior antipsychotic efficacy.

Discovery of a Potent, Orally Available, and Isoform-Selective Retinoic Acid β2 Receptor Agonist

Abstract: 4‘-Octyl-4-biphenylcarboxylic acid (1g, AC-55649) was identified as a highly isoform-selective agonist at the human RARβ2 receptor in a functional intact cell-based screening assay. The subsequent hit to lead optimization transformed the lipophilic, poorly soluble hit into a more potent and orally available compound (2, AC-261066) with retained β2 selectivity and greatly improved physiochemical properties. Being an isoform-selective RARβ2 receptor agonist that discriminates between nuclear receptor isoforms having identical ligand binding domains, 2 will be useful as a pharmacological research tool but also a valuable starting point for drug development.

Synthesis of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms

Abstract: Disclosed herein are methods for synthesizing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)-phenylmethyl)carbamide. Also disclosed herein is the hemi-tartrate salt of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)-phenylmethyl)carbamide and methods for obtaining the salt. Further disclosed are various crystalline forms of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)-phenylmethyl)carbamide and its hemi-tartrate salt including various polymorphs and solvates.

Salts of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and their preparation

Abstract: Disclosed herein are salts of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide of formula (I) including the citrate, fumarate, maleate, malate, phosphate, succinate, sulphate, and edisylate salts.

Selective serotonin receptor inverse agonists as therapeutics for disease

Abstract: Disclosed herein are pharmaceutical compositions comprising an inverse serotonin receptor agonist or a serotonin receptor antagonist and an anti-psychotic agent. Disclosed herein are also methods of treating psychotic disorders using the disclosed pharmaceutical compositions.

Androgen receptor modulators and method of treating disease using the same

Abstract: Disclosed herein are bicycloaryl compounds of Formula (I) that selectively modulate nuclear receptors, preferably the androgen receptor, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, and methods of treating disease comprising administering a compound of Formula (I) to a patient in need thereof.

Enabling tools to identify ligands for hormone nuclear receptors

Abstract: A method and kit developed to identify substances that act as ligands, corepressors, coactivators, agonist and antagonists for cloned nuclear hormone receptors, as well as a test kit for use in the methods is provided herein. More specifically, the method involves expressing a nuclear hormone receptor, receptor heterodimer, and/or receptor homodimer, DNA encoding one or more signaling molecules and DNA encoding a marker, incubating the cells with a test substance, and identifying whether the test substance interacts with the receptor quantitatively or qualitatively by identifying the amount of marker and/or the proliferation of the cells.

Compounds with activity at estrogen receptors

Abstract: Disclosed herein are novel di-phenyl compounds and methods for using various di-phenyl compounds for treatment and prevention of diseases and disorders related to estrogen receptors.

Reduction of haloperidol-induced side effects by ACP-103 in healthy volunteers

Abstract: Background/Aims A novel serotonin 2A (5-HT2A) receptor inverse agonist, ACP-103, was tested to determine the potential of ACP-103 to inhibit central nervous system side effects produced by haloperidol. Methods Healthy male volunteers participated in a randomized, double blind, placebo-controlled, single dose crossover study. All subjects received a single dose of haloperidol (7.5 mg) in combination with either a single dose of placebo or a single dose of ACP-103 (100 mg). The washout period between treatment combinations was two weeks. Results Haloperidol caused measurable akathisia in 13 of 18 subjects and induced approximately a 3-fold increase in prolactin secretion. ACP-103 treatment caused a measurable and temporally consistent decrease in haloperidol-induced akathisia compared to placebo treated subjects as measured by the Barnes Akathisia Scale. ACP-103 significantly reduced haloperidol-induced hyperprolactinemia. The pharmacokinetics of haloperidol and ACP-103 were not affected by their co-administration. No serious adverse events were reported. Conclusions Data suggest that ACP-103, when co-administered with existing antipsychotic drugs, may reduce their side effects and expand their range of efficacy. ACP-103 is being developed as an adjunctive therapy for schizophrenia and as a therapy for treatment-induced dysfunction in Parkinson's disease. Clinical Pharmacology & Therapeutics (2005) 77, P98–P98; doi: 10.1016/j.clpt.2005.01.004

Identification of ligands by selective amplification of cells transfected with a 5HT2A receptor

Abstract: The invention is directed to a method for identifying substances acting as ligands for transfected receptors by using transfected markers to measure receptor/ligand interactions. The present invention also relates to a method of identifying compounds which act as inverse agonists of the 5-HT2A receptor, the method comprising contacting a constitutively active 5-HT2A receptor with at least one test compound and determining any decrease in the amount of basal activity of the receptor so as to identify a test compound which is an inverse agonist of the 5-HT2A receptor. Such inverse agonists may be used in the treatment of schizophrenia and related psychoses.

Crystalline forms of n-desmethylclozapine

Abstract: Disclosed herein are crystalline Forms A, B, C, D, and E of N-desmethylclozapine, methods of preparing the same, pharmaceutical compositions comprising the same, and methods of therapeutic treatment involving N-desmethylclozapine polymorphic forms.

Methods to identify ligands of hormone nuclear receptors

Abstract: A method and kit developed to identify substances that act as ligands, corepressors, coactivators, agonist and antagonists for cloned nuclear hormone receptors, as well as a test kit for use in the methods is provided herein. More specifically, the method involves expressing a nuclear hormone receptor, receptor heterodimer, and/or receptor homodimer, DNA encoding one or more signaling molecules and DNA encoding a marker, incubating the cells with a test substance, and identifying whether the test substance interacts with the receptor quantitatively or qualitatively by identifying the amount of marker and/or the proliferation of the cells.

Crystalline form of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide hemi-tartrate

Abstract: A crystalline form of N- (4-fluorobenzyl) -N- (1-methylpiperidin-4-yl) -N '- (4- (2-methylpropyloxy) phenylmethyl) carbamide hemitertrate of formula IV, ** Formula ** which (a) shows an X-ray powder diffraction pattern comprising peaks that have d-enangstroms values of about 12.0, about 10.7, about 5.86, about 4.84, about 4, 70, about 4.57, and about 3.77; or (b) shows an endothermic signal near 177 ° C with a fusion enthalpy of about 129 J / g, as determined by differential scanning calorimetry.

Synthesis of a crystalline form of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide tartrate salt

Abstract: Disclosed herein are methods for synthesizing a crystalline form of hemitartrate salt of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy) phenylmethyl)carbamide and methods for obtaining the salt.