title: Dopamine autoreceptor agonists as potential antipsychotics. 2. (Aminoalkoxy)-4H-1-benzopyran-4-ones.
abstract: The synthesis and pharmacological properties of a novel type of [(arylpiperazinyl)alkoxy]-4H-1-benzopyran-4-ones with dopaminergic activity are described. The nature of the arylpiperazine (AP) moiety determines the dopamine (DA) agonist/antagonist character of this series of compounds; when the aryl portion of the AP is unsubstituted the compounds appear to be DA autoreceptor agonists while substituted aryl groups seem to impart DA antagonist activity. A heterocyclic piperazine, 7-[3-[4-(2-pyridinyl)-1-piperazinyl]propoxy]-4H-1-benzopyran-4-one (31, PD 119819) has been identified as an extremely selective DA autoreceptor agonist in tests that include [3H]haloperidol binding, inhibition of spontaneous locomotor activity, inhibition of brain DA synthesis, inhibition of brain DA neuronal firing, stereotypy assessment, and reversal of 6-hydroxydopamine (6-OHDA) induced akinesia in rats. In addition, 31 possesses good oral activity in the Sidman avoidance test in squirrel monkeys, a predictor of clinical antipsychotic efficacy. In another primate model, 31 has been found to lack the liability for extrapyramidal side effects observed with currently available antipsychotic drugs.
authors.affiliation: Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
authors.forename: J C
authors.initials: JC
authors.lastname: Jaen
authors.forename: L D
authors.initials: LD
authors.lastname: Wise
authors.forename: T G
authors.initials: TG
authors.lastname: Heffner
authors.forename: T A
authors.initials: TA
authors.lastname: Pugsley
authors.forename: L T
authors.initials: LT
authors.lastname: Meltzer
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis*; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D003863:Depression / Q000188:drug therapy; D004298:Dopamine / Q000096:biosynthesis; D015259:Dopamine Agents / Q000138:chemical synthesis*; D006220:Haloperidol / Q000378:metabolism; D007202:Indicators and Reagents; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship; D013569:Synapses / Q000502:physiology
chemical_list: D014150:Antipsychotic Agents; D001578:Benzopyrans; D015259:Dopamine Agents; D007202:Indicators and Reagents; D011954:Receptors, Dopamine; D006220:Haloperidol; D004298:Dopamine