ACADIA Pharmaceuticals Inc.

About: ACADIA Pharmaceuticals Inc. is a company organization based out in San Diego, California, United States. It is known for research contribution in the topics: Pimavanserin & Receptor. The organization has 260 authors who have published 276 publications receiving 8418 citations.

Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases

Abstract: Behavioral pharmacological data with the compound of formula (I), a novel and selective 5HT2A/2C receptor inverse agonist, demonstrate in vivo efficacy in models of psychosis and dyskinesias. This includes activity in reversing MK-801 induced locomotor behaviors, suggesting that this compound may be an efficacious anti-psychotic, and activity in an MPTP primate model of dyskinesias, suggesting efficacy as an anti-dyskinesia agent. These data support the hypothesis that 5HT2A/2C receptor inverse agonism may confer antipsychotic and anti-dyskinetic efficacy in humans, and indicate a use of the compound of formula (I) and related agents as novel therapeutics for Parkinson's Disease, related human neurodegenerative diseases, and psychosis.

Discovery of the first nonpeptide agonist of the GPR14/Urotensin-II receptor: 3-(4-Chlorophenyl)-3-(2-(dimethylamino)ethyl)isochroman-1-one (AC-7954)

Abstract: A functional cell-based screen identified 3-(4-chlorophenyl)-3-(2-(dimethylamino)ethyl)isochroman-1-one hydrochloride (AC-7954, 1) as a nonpeptidic agonist of the urotensin-II receptor. Racemic 1 had an EC50 of 300 nM at the human UII receptor and was highly selective. Testing of the enantiopure (+)- and (-)- 1 revealed that the UII receptor activity of racemic 1 resides primarily in (+)-1. Being a selective nonpeptidic druglike UII receptor agonist, (+)-1 will be useful as a pharmacological research tool and a potential drug lead.

ACP-103, a 5-Hydroxytryptamine 2A Receptor Inverse Agonist, Improves the Antipsychotic Efficacy and Side-Effect Profile of Haloperidol and Risperidone in Experimental Models

Abstract: Dopamine D2 receptor antagonism contributes to the therapeutic action of antipsychotic drugs (APDs) but also produces undesirable side effects, including extrapyramidal motor deficits, cognitive dulling, and prolactinemia. The introduction of atypical APDs was a significant advancement in the treatment of schizophrenia. Whereas these agents are D2 receptor antagonists, they are also potent 5-hydroxytryptamine (5-HT)2A receptor inverse agonists, a feature that may explain their improved efficacy and tolerability. Recently, we reported that N -(4-fluorophenylmethyl)- N -(1-methylpiperidin-4-yl)- N '-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2 R ,3 R )-dihydroxybutanedioate (2:1) (ACP-103), a novel selective 5-HT2A receptor inverse agonist that fails to bind D2 receptors, is active in several models predictive of antipsychotic activity. Using ACP-103, we tested the hypothesis that combining high levels of 5-HT2A inverse agonism with low levels of D2 antagonism would result in a favorable interaction, such that antipsychotic efficacy could be achieved with reduced D2 receptor-related adverse effects. Here we show that ACP-103 1) potently inhibited head-twitching produced by the 5-HT2A/2C receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine, 2) increased the potency of haloperidol against amphetamine-induced hyperactivity, 3) interacted synergistically with haloperidol or risperidone to suppress hyperactivity induced by the N -methyl-d-aspartate receptor antagonist (5 R ,10 S )-(+)-5-methyl-10,11-dihydro-5 H -dibenzo[ a , d ]cyclohepten-5,10-imine hydrogen maleate (MK-801), and, by contrast, 4) attenuated haloperido-l- or risperidone-induced prolactinemia. ACP-103 also attenuated catalepsy produced by haloperidol or risperidone. However, the doses that were required for this effect were higher than would be expected for a 5-HT2A receptor-mediated mechanism. These data indicate that utilizing ACP-103 as an adjunctive therapy to currently used APDs may result in enhanced antipsychotic efficacy while reducing adverse effects including those attributable to D2 receptor antagonism.