title: (+)-UH 232 and (+)-UH 242: novel stereoselective dopamine receptor antagonists with preferential action on autoreceptors.
abstract: The (+)- and (-)-enantiomers of the 2-aminotetralin derivatives cis-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin (UH 232) and cis-5-hydroxy-1-methyl-2-(di-n-propylamino)tetralin (UH 242), were pharmacologically evaluated in rats in an extensive series of in vivo biochemical and behavioral experiments. These studies showed that the (+)- and (-)-enantiomers have differential effects on central dopamine (DA) receptors. Thus, (-)-UH 242 is a DA-receptor agonist stimulating both pre- and postsynaptic receptors. (-)-UH 232 is also active as a DA receptor agonist, although with much lower potency than (-)-UH 242. In contrast, (+)-UH 242 and (+)-UH 232 are characterized as DA receptor antagonists. Both (+) forms markedly accelerated DA synthesis and turnover and reversed the biochemical and behavioral effects of apomorphine. Locomotor activity was stimulated by the (+)-enantiomers over a wide dose range; hypomotility was induced only by high doses. The pharmacological profile of the (+)-enantiomers clearly differs from that of classical neuroleptics and suggests a preferential antagonistic action on DA autoreceptors. (+)-UH 232 and (+)-UH 242 may prove useful as experimental tools and as potential therapeutic agents (selectively increasing DA-ergic neurotransmission), e.g. in geriatric practice.
authors.forename: K
authors.initials: K
authors.lastname: Svensson
authors.forename: S
authors.initials: S
authors.lastname: Hjorth
authors.forename: D
authors.initials: D
authors.lastname: Clark
authors.forename: A
authors.initials: A
authors.lastname: Carlsson
authors.forename: H
authors.initials: H
authors.lastname: Wikström
authors.forename: B
authors.initials: B
authors.lastname: Andersson
authors.forename: D
authors.initials: D
authors.lastname: Sanchez
authors.forename: A M
authors.initials: AM
authors.lastname: Johansson
authors.forename: L E
authors.initials: LE
authors.lastname: Arvidsson
authors.forename: U
authors.initials: U
authors.lastname: Hacksell
mesh_terms: D015107:4-Butyrolactone / Q000494:pharmacology; D006916:5-Hydroxytryptophan / Q000096:biosynthesis; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000031:analogs & derivatives*; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D004295:Dihydroxyphenylalanine / Q000096:biosynthesis; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D009043:Motor Activity; D009281:Naphthalenes / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism*; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D013237:Stereoisomerism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
chemical_list: D009281:Naphthalenes; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; D012701:Serotonin; D004295:Dihydroxyphenylalanine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D012110:Reserpine; C045971:UH 232; C045972:5-hydroxy-1-methyl-2-(di-n-propylamino)tetralin; D006916:5-Hydroxytryptophan; D001058:Apomorphine; D015107:4-Butyrolactone; D004298:Dopamine; D009638:Norepinephrine