Dopamine Autoreceptor Agonists as Potential Antipsychotics. 3. 6-Propyl-4,5,5a,6,7,8-hexahydrothiazoloquinolin-2-amine

Article abstract of DOI:10.1021/jm00113a010

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 γ-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).