Dopamine autoreceptor agonists as potential antipsychotics. 3.6-Propyl-4,5,5a,6,7,8-hexahydrothiazolo[4,5-f]quinolin-2-amine.
A series of rigid tricyclic analogues of the dopamine (DA) agonist PD 118440 [4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine] was synthesized and evaluated for dopaminergic activity and DA autoreceptor selectivity. (R)-(+)-6-Propyl-4,5,5a,6,7,8-hexahydrothiazolo[4,5-f]quinolin+ ++-2-amine [+)-6) was identified as the most selective DA autoreceptor agonist from this group of compounds. It inhibited spontaneous locomotor activity (LMA) in rodents, reversed the gamma-butyrolactone (GBL) induced accumulation of rat striatal DOPA and inhibited brain DA neuronal firing, all suggestive of direct DA autoreceptor agonist activity. However, (+)-6 is not completely free of postsynaptic DA activity, as evidenced by its stimulation of LMA in rats at high doses and its ability to produce stereotypy. On the other hand, (-)-6 appears to be a weak partial DA agonist with some effects on brain DA synthesis only at high doses. Like other DA autoreceptor agonists and DA antagonists, (+)-6 inhibited Sidman conditioned avoidance in squirrel monkeys, a test predictive of clinical antipsychotic activity. However, unlike classical antipsychotics, (+)-6 did not induce dystonias in haloperidol-sensitized squirrel monkeys, suggesting a minimal propensity toward extrapyramidal side effects (EPS).
Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
B W
BW
Caprathe
J C
JC
Jaen
L D
LD
Wise
T G
TG
Heffner
T A
TA
Pugsley
L T
LT
Meltzer
M
M
Parvez
D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry; D015259:Dopamine Agents / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D051381:Rats; D013237:Stereoisomerism
D014150:Antipsychotic Agents; D015259:Dopamine Agents