title: Evaluation of the effects of the enantiomers of reduced haloperidol, azaperol, and related 4-amino-1-arylbutanols on dopamine and sigma receptors.
abstract: The enantiomers of reduced haloperidol (3a), azaperol (3b), and the related compound BMY-14802 (3c) were prepared in high optical purity. The affinity of these compounds for dopamine D2 and D3 receptors, and sigma S1 and S2 sites was determined in vitro. Both enantiomers of 3a display greatly decreased affinity for D2 and D3 receptors compared to haloperidol, although they still possess affinities in the 100-200-nM range. Both enantiomers of 3a possess potent and equal affinity for S1 sites (Ki: 1-2 nM), only slightly weaker than haloperidol (Ki: 0.33 nM). At S2 sites, (R)-(+)-3a displays similar affinity to haloperidol (Ki: 31 and 26 nM, respectively), while (S)-(-)-3a is slight more potent (Ki: 8.2 nM). The stereoselectivity profile of the enantiomers of 3b at D2 and D3 receptors is quite similar to that of 3a, (S)-(-)-3b being about 4 times more potent than its enantiomer at both receptors. (R)-(+)-3b binds preferentially to sigma S1 over S2 sites, while (S)-(-)-3b displays the opposite selectivity profile. Both enantiomers of 3c possess very weak affinity for D2 and D3 receptors. In a manner similar to the enantiomers of 3b, the affinity of (R)-(+)-3c is greater for S1 than S2 sites, while (S)-(-)-3c displays the opposite selectivity profile. Following parenteral administration of both enantiomers of 3a, dopamine synthesis and turnover in rat striatum, cortex, and mesolimbic areas were increased, in a manner similar to the effects produced by haloperidol itself. Additional studies will be required to assess with certainty whether the effects were due to the compounds themselves or simply were a consequence of the in vivo oxidation to haloperidol.
authors.affiliation: Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105.
authors.forename: J C
authors.initials: JC
authors.lastname: Jaen
authors.forename: B W
authors.initials: BW
authors.lastname: Caprathe
authors.forename: T A
authors.initials: TA
authors.lastname: Pugsley
authors.forename: L D
authors.initials: LD
authors.lastname: Wise
authors.forename: H
authors.initials: H
authors.lastname: Akunne
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000440:Butanols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D004298:Dopamine / Q000096:biosynthesis; D018492:Dopamine Antagonists; D006168:Guinea Pigs; D006220:Haloperidol / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006719:Homovanillic Acid / Q000378:metabolism; D006801:Humans; D008297:Male; D010084:Oxidation-Reduction; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D050637:Receptors, Dopamine D3; D017480:Receptors, sigma / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D014150:Antipsychotic Agents; D000440:Butanols; C493593:DRD3 protein, human; D018492:Dopamine Antagonists; C493595:Drd3 protein, rat; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D017480:Receptors, sigma; D015102:3,4-Dihydroxyphenylacetic Acid; C050408:alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol; C084681:azaperol; D006220:Haloperidol; D004298:Dopamine; D006719:Homovanillic Acid