Showing papers by "ACADIA Pharmaceuticals Inc. published in 2006"

Pharmacological and Behavioral Profile of N-(4-Fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl) Carbamide (2R,3R)-Dihydroxybutanedioate (2:1) (ACP-103), a Novel 5-Hydroxytryptamine2A Receptor Inverse Agonist

Abstract: The in vitro and in vivo pharmacological properties of N -(4-fluorophenylmethyl)- N -(1-methylpiperidin-4-yl)- N ′-(4-(2-methylpropyloxy)phenylmethyl)carbamide (2 R ,3 R )-dihydroxybutanedioate (2:1) (ACP-103) are presented. A potent 5-hydroxytryptamine (5-HT)2A receptor inverse agonist ACP-103 competitively antagonized the binding of [3H]ketanserin to heterologously expressed human 5-HT2A receptors with a mean p K i of 9.3 in membranes and 9.70 in whole cells. ACP-103 displayed potent inverse agonist activity in the cell-based functional assay receptor selection and amplification technology (R-SAT), with a mean pIC50 of 8.7. ACP-103 demonstrated lesser affinity (mean p K i of 8.80 in membranes and 8.00 in whole cells, as determined by radioligand binding) and potency as an inverse agonist (mean pIC50 7.1 in R-SAT) at human 5-HT2C receptors, and lacked affinity and functional activity at 5-HT2B receptors, dopamine D2 receptors, and other human monoaminergic receptors. Behaviorally, ACP-103 attenuated head-twitch behavior (3 mg/kg p.o.), and prepulse inhibition deficits (1-10 mg/kg s.c.) induced by the 5-HT2A receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride in rats and reduced the hyperactivity induced in mice by the N -methyl-d-aspartate receptor noncompetitive antagonist 5 H -dibenzo[ a , d ]cyclohepten-5,10-imine (dizocilpine maleate; MK-801) (0.1 and 0.3 mg/kg s.c.; 3 mg/kg p.o.), consistent with a 5-HT2A receptor mechanism of action in vivo and antipsychotic-like efficacy. ACP-103 demonstrated >42.6% oral bioavailability in rats. Thus, ACP-103 is a potent, efficacious, orally active 5-HT2A receptor inverse agonist with a behavioral pharmacological profile consistent with utility as an antipsychotic agent.

Structural Requirements of Transmembrane Domain 3 for Activation by the M1 Muscarinic Receptor Agonists AC-42, AC-260584, Clozapine and N-desmethylclozapine: Evidence for three distinct modes of receptor activation

Abstract: Transmembrane domain 3 (TM3) plays a crucial role mediating muscarinic acetylcholine receptor activation by acetylcholine, carbachol, and other muscarinic agonists. We compared the effects of point mutations throughout TM3 on the interactions of carbachol, 4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl] piperidine hydrogen chloride (AC-42), a potent structural analog of AC-42 called 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (AC-260584), N-desmethylclozapine, and clozapine with the M1 muscarinic receptor. The binding and activation profiles of these ligands fell into three distinct patterns; one exemplified by orthosteric compounds like carbachol, another by structural analogs of AC-42, and a third by structural analogs of N-desmethylclozapine. All mutations tested severely reduced carbachol binding and activation of M1. In contrast, the agonist actions of AC-42 and AC-260584 were greatly potentiated by the W101A mutation, slightly reduced by Y106A, and slightly increased by S109A. Clozapine and N-desmethylclozapine displayed substantially increased maximum responses at the Y106A and W101A mutants, slightly lower activity at S109A, but no substantial changes in potency. At L102A and N110A, agonist responses to AC-42, AC-260584, clozapine, and N-desmethylclozapine were all substantially reduced, but usually less than carbachol. D105A showed no functional responses to all ligands. Displacement and dissociation rate experiments demonstrated clear allosteric properties of AC-42 and AC-260584 but not for N-desmethylclozapine and clozapine, indicating that they may contact different residues than carbachol to activate M1 but occupy substantially overlapping spaces, in contrast to AC-42 and AC-260584, which occupy separable spaces. These results show that M1 receptors can be activated in at least three distinct ways and that there is no requirement for potent muscarinic agonists to mimic acetylcholine interactions with TM3.

Characterization of the Mas-related gene family: structural and functional conservation of human and rhesus MrgX receptors.

Abstract: Recently, a large family of G-protein-coupled receptors called Mas-related genes (Mrgs), which is selectively expressed in small-diameter sensory neurons of dorsal root ganglia, was described. A subgroup of human Mrg receptors (MrgX1-X4) is not found in rodents and this has hampered efforts to define the physiological roles of these receptors. MrgX receptors were cloned from rhesus monkey and functionally characterized alongside their human orthologs. Most of the human and rhesus MrgX receptors displayed high constitutive activity in a cellular proliferation assay. Proliferative responses mediated by human or rhesus MrgX1, or rhesus MrgX2 were partially blocked by pertussis toxin (PTX). Proliferative responses mediated by rhesus MrgX3 and both human and rhesus MrgX4 were PTX insensitive. These results indicate that human and rhesus MrgX1 and MrgX2 receptors activate both Gq- and Gi-regulated pathways, while MrgX3 and MrgX4 receptors primarily stimulate Gq-regulated pathways. Peptides known to activate human MrgX1 and MrgX2 receptors activated the corresponding rhesus receptors in cellular proliferation assays, Ca(2+)-mobilization assays, and GTP-gammaS-binding assays. Cortistatin-14 was selective for human and rhesus MrgX2 receptors over human and rhesus MrgX1 receptors. BAM22 and related peptides strongly activated human MrgX1 receptors, but weakly activated rhesus MrgX1, human MrgX2, and rhesus MrgX2 receptors. These data suggest that the rhesus monkey may be a suitable animal model for exploring the physiological roles of the MrgX receptors.

Pharmacological profiles of opioid ligands at kappa opioid receptors.

Abstract: The aim of the present study was to describe the activity of a set of opioid drugs, including partial agonists, in a human embryonic kidney cell system stably expressing only the mouse κ-opioid receptors. Receptor activation was assessed by measuring the inhibition of cyclic adenosine mono phosphate (cAMP) production stimulated by 5 μM forskolin. Intrinsic activities and potencies of these ligands were determined relative to the endogenous ligand dynorphin and the κ agonist with the highest intrinsic activity that was identified in this study, fentanyl. Among the ligands studied naltrexone, WIN 44,441 and dezocine, were classified as antagonists, while the remaining ligands were agonists. Intrinsic activity of agonists was assessed by determining the extent of inhibition of forskolin-stimulated cAMP production. The absolute levels of inhibition of cAMP production by each ligand was used to describe the rank order of intrinsic activity of the agonists; fentanyl = lofentanil ≥ hydromorphone = morphine = nalorphine ≥ etorphine ≥ xorphanol ≥ metazocine ≥ SKF 10047 = cyclazocine ≥ butorphanol > nalbuphine. The rank order of affinity of these ligands was; cyclazocine > naltrexone ≥ SKF 10047 ≥ xorphanol ≥ WIN 44,441 > nalorphine > butorphanol > nalbuphine ≥ lofentanil > dezocine ≥ metazocine ≥ morphine > hydromorphone > fentanyl. These results elucidate the relative activities of a set of opioid ligands at κ-opioid receptor and can serve as the initial step in a systematic study leading to understanding of the mode of action of these opioid ligands at this receptor.

Constitutive activity of muscarinic acetylcholine receptors

Abstract: We review the literature describing constitutive activity of the five muscarinic acetylcholine receptors in native and recombinant systems and discuss the effect of constitutive activity on muscarinic pharmacology in the context of modern models of receptor activation. We include a summary of mutations found to cause constitutive activity and discuss the implications of these data for the structure, function, and activation mechanism of muscarinic receptors. Finally, we discuss the possible physiological significance of constitutive activity of muscarinic receptors, incorporating information provided by targeted deletion of each of the muscarinic subtypes.

Integrative functional assays, chemical genomics and high throughput screening: harnessing signal transduction pathways to a common HTS readout.

Abstract: Chemical genomics is a drug discovery strategy that relies heavily on high-throughput screening (HTS) and therefore benefits from functional assay platforms that allow HTS against all relevant genomic targets. Receptor Selection and Amplification Technology (R-SAT™) is a cell-based, high-throughput functional assay where the receptor stimulus is translated into a measurable cellular response through an extensive signaling cascade occurring over several days. The large biological and chronological separation of stimulus from response provides numerous opportunities for enabling assays and increasing assay sensitivity. Here we review strategies for building homogeneous assay platforms across large gene families by redirecting and/or amplifying signal transduction pathways.

Functional bioluminescence energy resonance transfer (bret) assay to screen, identify and characterize receptor tyrosine kinase ligands

Abstract: Disclosed herein are methods of evaluating whether a test compound functions as a ligand for a receptor tyrosine kinase Also provided are methods of making pharmaceutical compositions that include agonists, antagonists, or inverse agonists of receptor tyrosine kinases Also provides are isolated cells that include a receptor tyrosine kinase and a second protein, wherein the receptor tyrosine kinase contains a fluorescent donor moiety and the second protein contains a fluorescent acceptor moiety

Cb-1 modulating compounds and their use

Abstract: Disclosed herein is a compound of Formula (I) Also disclosed herein is a method of modulating the activity of a cannabinoid receptor using a compound of Formula (I) Furthermore, disclosed herein is a method of treating a disease or condition that would be alleviated, improved or prevented by administration of a compound that modulates a cannabinoid receptor comprising identifying a subject in need thereof and administering to said subject a therapeutically effective amount of a compound of Formula (I) Also disclosed herein are pharmaceutical compositions comprising a compound of Formula (I)

Novel potent and efficacious nonpeptidic urotensin II receptor agonists

Abstract: Six different series of nonpeptidic urotensin II receptor agonists have been synthesized and evaluated for their agonistic activity in a cell-based assay (R-SAT). The compounds are ring-opened analogues of the isochromanone-based agonist AC-7954 with different functionalities constituting the linker between the two aromatic ring moieties. Several of the compounds are highly potent and efficacious, with N-[1-(4-chlorophenyl)-3-(dimethylamino)-propyl]-4-phenylbenzamide oxalate (5d) being the most potent. The pure enantiomers of 5d were obtained from the corresponding diastereomeric amides. It was shown by a combination of X-ray crystallography and chemical correlation that the activity resides in the S-enantiomer of 5d (pEC50 7.49).

Beta-arrestin 2 modulates the activity of nuclear receptor RAR beta2 through activation of ERK2 kinase.

Abstract: The activity of retinoid receptors activity can be regulated by various extracellular stimuli. In an effort to understand the molecular basis for this phenomenon, the role of β-arrestins was investigated. β-Arrestins constitute a class of proteins involved in the internalization of agonist-activated receptors. They have also been linked to MAPK activation suggesting a direct involvement in signaling cascades. Here, we report that β-arrestin 2 stimulates the transcriptional activation of the retinoid RAR and RXR receptors. Of all the retinoid receptors, the RAR β2 subtype showed the strongest sensitivity to β-arrestin 2 action. Interestingly, this event requires the presence of the MAP kinase ERK2, but not that of JNK or P38. Site-directed mutagenesis showed that Ser 22 and Leu 217 are critical residues of the RAR β2 receptor through which β-arrestin 2 effects are mediated. More importantly, we demonstrate that the induction of PC12 growth inhibition by Nerve Growth Factor is indeed dependent upon RAR β2 transcriptional activation in a β-arrestin 2- and ERK2-dependent manner.

Bicyclic nitrogen compounds as modulators of ghrelin receptor and uses thereof

Abstract: Disclosed herein are compounds of Formula I as defined herein, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, that modulates the activity of a ghrelin receptor. Disclosed herein are also methods of treating diseases or conditions that comprise administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I.

Aminophenyl derivatives as selective androgen receptor modulators

Abstract: Disclosed herein is a novel class of aminophenyl compounds having the structure (I) wherein R1 is cyano or nitro and ring A is a bi- or tricyclic bridged heterocycle and to their use as modulators of androgen receptor for the treatment or prevention of conditions relating thereto

PAR2-modulating compounds and their use

Abstract: The present invention relates to compounds, and uses thereof, having the chemical formula: or a pharmaceutically acceptable salt or prodrug thereof, wherein the compound modulates the activity of PAR2 or a PAR2 subtype and thereby may be used to treat or prevent diseases involving abnormal PAR2 or PAR2 subtype activity.

PAR2-modulating compounds and their use

Abstract: This invention relates to compounds, their uses for the elucidation of PAR2 activity and their uses for the treatment or prevention of diseases or disorders related to PAR2 activity, wherein the compound has the general chemical structure:

Use of n-desmethylclozapine and related compounds as dopamine stabilizing agents

Abstract: Disclosed herein is the use of N-desmethylclozapine (NDMC) and related compounds to treat a variety of neuropsychiatric diseases including psychosis. It is shown that NDMC and related compounds are agonists or partial agonists at D2 and D3 dopamine receptors and thus may be effective as a dopamine stabilizing agent, allowing it to be used to treat or provide reduced incidence of Extrapyramidal symptoms (EPS) and/or tardive dyskinesias (TD). Also disclosed is administering NDMC and related compounds in combination with other anti-psychotic agents.

Prodrugs of muscarinic agonists and methods of treatment of neuropsychiatric disorders

Abstract: Compounds are described that are prodrugs to active compounds that modulate a muscarinic receptor. In some cases, the compounds are prodrugs to N-desmethylclozapine. The compounds may be used to treat neuropsychiatric disorders.

Uii-modulating compounds and their use

Abstract: Disclosed herein are novel aromatic-containing compounds and methods for using various aromatic-containing compounds for treatment and prevention of diseases and disorders related to the Urotensin II receptor

Method of synthesis and isolation of solid N-desmethylclozapine and crystalline forms thereof

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.

Iron catalyzed cross-coupling reactions of imidoyl derivatives

Abstract: Disclosed is a process for preparing a compound of formula A - N=C(D)(B), from a compound of formula A-N=C(E)(B) and a compound of formula D-M using an iron catalyst, where the process has is represented by Equation (I).

Triazadibenzoazulene compounds useful for the treatment and prevention of pain and screening methods therefor compounds useful for the treatment and prevention of pain and screening methods therefor

Abstract: The present invention relates to compounds having the generic structure (I): and to a method of treatment or prevention of pain using the above compounds.

Compounds useful for the treatment and prevention of pain and screening methods therefor

Abstract: The present invention relates to the composition of compounds having the generic structure: and to a method of treatment or prevention of pain using the above compounds.

Iron-Catalyzed Cross-Coupling of Imidoyl Chlorides with Grignard Reagents.

Abstract: A general, high yielding rapid iron-catalyzed cross-coupling reaction between Grignard reagents and imidoyl chlorides is described. These reactions are typically completed within 5 min, resulting in high yields of 71−96% using 5% iron catalyst in a THF−NMP solvent mixture. Functionalized imidoyl chlorides (e.g., R = CO2Me) gave excellent yields (89%).

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

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.