Synthesis, beta-adrenergic activity, and platelet antiaggregatory activity of a positional isomer of trimetoquinol: 1-(2',4',5'-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4,-tetrahydroisoquinoline.

A positional isomer of trimetoquinol (1), 1-(2',4',5'-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (3), was synthesized and found to possess less beta-adrenergic activity than 1 in isolated guinea pig atrial and tracheal preparations. The analogue 3 was an effective antiaggregatory agent in human and rabbit platelet-rich plasma preparations, while 1 was effective only as an inhibitor of arachidonic acid induced aggregation in human platelets. These findings indicate that both qualitative and quantitative differences in biological activity have occurred as a result of changing the position of the methoxy groups on the 1-benzyl substituent of 1.

Synthesis and evaluation of substituted 2-phenylcyclobutylamines as analogues of hallucinogenic phenethylamines: lack of LSD-like biological activity.

cis- and trans-2-(2,4,5-trimethoxyphenyl)cyclobutylamine and trans-2-(2,5-dimethoxy-4-methylphenyl)cyclobutylamine were synthesized as conformationally restricted analogues of hallucinogenic phenylisopropylamines. In rats trained to discriminate saline from LSD (0.08 mg/kg, ip) in a two-lever drug discrimination paradigm, no generalization of the LSD stimulus to the cis trimethoxy compound occurred at doses up to 20 mg/kg. For both of the trans compounds, partial generalization of the LSD cue occurred at doses of 5 mg/kg or greater. In contrast, complete generalization occurred with trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine. The ED50 for this compound and the doses of the trans cyclobutyl homologues at which significant drug-appropriate responding occurred indicate that the latter are on the order of 50-75 times less potent than the cyclopropylamine analogue. The lack of generalization to the cyclobutylamines indicates either that their discriminative stimulus properties differ from LSD or that they lack discriminative effects.

Conformation of dopamine at the dopamine receptor.

Tritiated dopamine was used to label the dopamine receptor in membranes isolated from the rat corpus striatum. Scatchard analysis of displacement of [3H]dopamine by nonradioactive dopamine indicated the presence of two binding sites. The similarities in affinity, capacity, and drug specificity of the high-affinity site in the striatal membranes from rat and the binding site in the membranes from the calf caudate nucleus suggest that [3H]dopamine labels the same site in both species. In order to determine what conformation of dopamine is preferred at the dopamine receptor site, conformationally restricted analogs of dopamine--namely, the cis and trans 2-amino-1(3,4-dihydroxyphenyl)cyclobutane hydrochlorides--were tested for their affinity to the receptor. Compared to the cis conformation, the trans-restricted analogs had more affinity for the receptor site, indicating that dopamine probably interacts with the receptor in the trans conformation.