title: 5-hydroxytryptamine2A receptor inverse agonists as antipsychotics.
abstract: We have used a cell-based functional assay to define the pharmacological profiles of a wide range of central nervous system active compounds as agonists, competitive antagonists, and inverse agonists at almost all known monoaminergic G-protein-coupled receptor (GPCR) subtypes. Detailed profiling of 40 antipsychotics confirmed that as expected, most of these agents are potent competitive antagonists of the dopamine D2 receptor. Surprisingly, this analysis also revealed that most are potent and fully efficacious 5-hydroxytryptamine (5-HT)2A receptor inverse agonists. No other molecular property was shared as universally by this class of compounds. Furthermore, comparisons of receptor potencies revealed that antipsychotics with the highest extrapyramidal side effects (EPS) liability are significantly more potent at D2 receptors, the EPS-sparing atypical agents had relatively higher potencies at 5-HT2A receptors, while three were significantly more potent at 5-HT2A receptors. Functional high-throughput screening of a diverse chemical library identified 530 ligands with inverse agonist activity at 5-HT2A receptors, including several series of compounds related to known antipsychotics, as well as a number of novel chemistries. An analog of one of the novel chemical series, AC-90179, was pharmacologically profiled against the remaining monoaminergic GPCRs and found to be a highly selective 5-HT2A receptor inverse agonist. The behavioral pharmacology of AC-90179 is characteristic of an atypical antipsychotic agent.
authors.affiliation: ACADIA Pharmaceuticals Inc., San Diego, California 92121, USA. dweiner@acadia-pharm.com
authors.forename: D M
authors.initials: DM
authors.lastname: Weiner
authors.forename: E S
authors.initials: ES
authors.lastname: Burstein
authors.forename: N
authors.initials: N
authors.lastname: Nash
authors.forename: G E
authors.initials: GE
authors.lastname: Croston
authors.forename: E A
authors.initials: EA
authors.lastname: Currier
authors.forename: K E
authors.initials: KE
authors.lastname: Vanover
authors.forename: S C
authors.initials: SC
authors.lastname: Harvey
authors.forename: E
authors.initials: E
authors.lastname: Donohue
authors.forename: H C
authors.initials: HC
authors.lastname: Hansen
authors.forename: C M
authors.initials: CM
authors.lastname: Andersson
authors.forename: T A
authors.initials: TA
authors.lastname: Spalding
authors.forename: D F
authors.initials: DF
authors.lastname: Gibson
authors.forename: K
authors.initials: K
authors.lastname: Krebs-Thomson
authors.forename: S B
authors.initials: SB
authors.lastname: Powell
authors.forename: M A
authors.initials: MA
authors.lastname: Geyer
authors.forename: U
authors.initials: U
authors.lastname: Hacksell
authors.forename: M R
authors.initials: MR
authors.lastname: Brann
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003001:Cloning, Molecular; D004353:Drug Evaluation, Preclinical; D019204:GTP-Binding Proteins / Q000378:metabolism; D005784:Gene Amplification; D019416:Head Movements / Q000187:drug effects; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects*; D013216:Reflex, Startle / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D019204:GTP-Binding Proteins