title: 4-(1,2,5,6-Tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamines: a novel class of compounds with central dopamine agonist properties.
abstract: The design, synthesis, and pharmacological properties of a novel type of 4-(1,2,5,6-tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamine with dopaminergic properties are described. In particular, 4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine (4c, PD 118440) and its allyl analogue (4i, PD 120697) have been identified as orally active dopamine (DA) agonists with pronounced central nervous system effects in tests that include [3H]-haloperidol and [3H]-N-propylnorapomorphine binding, inhibition of striatal DA synthesis, inhibition of DA neuronal firing, inhibition of spontaneous locomotor activity, and reversal of reserpine-induced depression in rats. The DA autoreceptor selectivity of these heterocyclic analogues of 3-(1-propyl-3-piperidinyl)phenol (3-PPP) was also evaluated. In this series, DA agonist activity was found to be highly dependent on the size of the N-alkyl substituent, the saturation level of the six-membered ring, and the mode of attachment of the 2-aminothiazole ring.
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: B W
authors.initials: BW
authors.lastname: Caprathe
authors.forename: H
authors.initials: H
authors.lastname: Tecle
authors.forename: S
authors.initials: S
authors.lastname: Bergmeier
authors.forename: C C
authors.initials: CC
authors.lastname: Humblet
authors.forename: T G
authors.initials: TG
authors.lastname: Heffner
authors.forename: L T
authors.initials: LT
authors.lastname: Meltzer
authors.forename: T A
authors.initials: TA
authors.lastname: Pugsley
mesh_terms: D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D004295:Dihydroxyphenylalanine / Q000096:biosynthesis; D004298:Dopamine / Q000096:biosynthesis; D015259:Dopamine Agents; D006220:Haloperidol / Q000378:metabolism; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000502:physiology; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects / Q000502:physiology; D017448:Receptors, Dopamine D2; D013329:Structure-Activity Relationship; D013378:Substantia Nigra / Q000502:physiology; D013816:Thermodynamics; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D015259:Dopamine Agents; D011725:Pyridines; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D013844:Thiazoles; C062454:PD 118440; C062455:PD 120697; C009074:N-n-propylnorapomorphine; D004295:Dihydroxyphenylalanine; D006220:Haloperidol; D001058:Apomorphine; D004298:Dopamine