title: Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity.
abstract: Ziprasidone (CP-88,059) is a combined 5-HT (serotonin) and dopamine receptor antagonist which exhibits potent effects in preclinical assays predictive of antipsychotic activity. Whereas the compound is a dopamine antagonist in vitro and in vivo, its most potent action is antagonism of 5-HT2A receptors, where its affinity is an order of magnitude greater than that observed for dopamine D2 sites. Laboratory and clinical findings have led to a hypothesis that antagonism of 5-HT2A receptors in the brain limits the undesirable motor side effects associated with dopamine receptor blockade and improves efficacy against the negative symptoms of schizophrenia. Ziprasidone possesses an in vitro 5-HT2A/dopamine D2 receptor affinity ratio higher than any clinically available antipsychotic agent. In vivo, ziprasidone antagonizes 5-HT2A receptor-induced head twitch with 6-fold higher potency than for blockade of d-amphetamine-induced hyperactivity, a measure of central dopamine D2 receptor antagonism. Ziprasidone also has high affinity for the 5-HT1A, 5-HT1D and 5-HT2C receptor subtypes, which may further enhance its therapeutic potential. The prediction of antipsychotic efficacy without severe motor side effects is supported by the relatively weak potency of ziprasidone to produce catalepsy in animals, contrasted with its potent antagonism of conditioned avoidance responding and dopamine agonist-induced locomotor activation and stereotypy. The compound is well tolerated in animals at doses producing effective dopamine antagonism in the brain. Ziprasidone should be a valuable addition to the treatment of psychotic disorders.
authors.affiliation: Central Research Division, Pfizer Inc., Groton, CT, USA.
authors.forename: T F
authors.initials: TF
authors.lastname: Seeger
authors.forename: P A
authors.initials: PA
authors.lastname: Seymour
authors.forename: A W
authors.initials: AW
authors.lastname: Schmidt
authors.forename: S H
authors.initials: SH
authors.lastname: Zorn
authors.forename: D W
authors.initials: DW
authors.lastname: Schulz
authors.forename: L A
authors.initials: LA
authors.lastname: Lebel
authors.forename: S
authors.initials: S
authors.lastname: McLean
authors.forename: V
authors.initials: V
authors.lastname: Guanowsky
authors.forename: H R
authors.initials: HR
authors.lastname: Howard
authors.forename: J A
authors.initials: JA
authors.lastname: Lowe
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000661:Amphetamine / Q000037:antagonists & inhibitors; D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology*; D001058:Apomorphine / Q000037:antagonists & inhibitors; D001522:Behavior, Animal / Q000187:drug effects; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D002375:Catalepsy / Q000139:chemically induced; D002417:Cattle; D002831:Choroid Plexus / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D011814:Quipazine / Q000037:antagonists & inhibitors; D051381:Rats; D011941:Receptors, Adrenergic / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism / Q000502:physiology; D011985:Receptors, Serotonin / Q000378:metabolism / Q000502:physiology; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*; D013552:Swine; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D015306:Biogenic Monoamines; D018492:Dopamine Antagonists; D014179:Neurotransmitter Uptake Inhibitors; D010879:Piperazines; D011941:Receptors, Adrenergic; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013844:Thiazoles; D011814:Quipazine; C092292:ziprasidone; D000661:Amphetamine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D001058:Apomorphine