PT  - JOURNAL ARTICLE
AU  - D. M. Weiner
AU  - E. S. Burstein
AU  - N. Nash
AU  - G. E. Croston
AU  - E. A. Currier
AU  - K. E. Vanover
AU  - S. C. Harvey
AU  - E. Donohue
AU  - H. C. Hansen
AU  - C. M. Andersson
AU  - T. A. Spalding
AU  - D. F. C. Gibson
AU  - K. Krebs-Thomson
AU  - S. B. Powell
AU  - M. A. Geyer
AU  - U. Hacksell
AU  - M. R. Brann
TI  - 5-Hydroxytryptamine<sub>2A</sub> Receptor Inverse Agonists as Antipsychotics
DP  - 2001 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 268--276
VI  - 299
IP  - 1
4099  - http://jpet.aspetjournals.org/content/299/1/268.short
4100  - http://jpet.aspetjournals.org/content/299/1/268.full
SO  - J Pharmacol Exp Ther2001 Oct 01; 299
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics