5HT2A RECEPTOR INVERSE AGONISTS AS NOVEL ANTIPSYCHOTICS

Arena Pharmaceuticals, San Diego CA

Investigators

Abstract

Clozapine is the prototypical "atypical" antipsychotic agent. This therapeutic provides relief from the delusional and depressive symptoms of schizophrenia without producing the severe side-effects which characterized the typical antipsychotics. Recent advances in the molecular biology of monoaminergic receptors has revealed "inverse agonist" properties of atypical drugs, such as clozapine, at the serotonin 5-HT2A receptor. Inverse agonism affords drugs the ability to block ligand-independent activity of receptors by destabilizing the active conformation of the receptor protein. We propose to use recombinant DNA technology to produce a constitutively active form of the human 5-HT2A receptor which will be used to screen for specific novel 5- HT2A receptor inverse agonists. Site-directed mutagenesis will be employed to substitute specific amino acids involved in constraining the wild type human 5-HT2A receptor in the inactive conformation. The resulting constitutively active 5-HT2A receptor will be employed to screen a small molecule chemical library to directly identify 5-HT2A inverse agonists. Identified molecules will be further modified chemically to produce high potency 5-HT2A receptor inverse agonists. The overall purpose of this proposal is to identify potent molecules which will be further developed as potential novel antipsychotic agents.