Tritiated dopamine was used to label the dopamine receptor in membranes isolated from the rat corpus striatum. Scatchard analysis of displacement of [3Hldopamine 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 [3Hjdopamine 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.There is considerable interest in the relationship between conformation of neurotransmitters at their receptors and biological activity (1, 2). The putative neurotransmitter dopamine is probably involved in parkinsonism (3), Huntington chorea (4), drug-induced dyskinesia (5, 6), schizophrenia (7), and manic depressive psychosis (8,9). The preferred conformation of dopamine in the solid state is the trans extended form, and in solution it exists primarily in the trans and gauche conformations with the trans form being slightly predominant (10, 11).However, it is realized that the preferred conformation of dopamine in the dopamine-receptor complex need not be the same as that in solution or in the solid state (11, 2). Nevertheless, investigations with dopamine-sensitive adenylate cyclase support the idea that the trans extended form of dopamine interacts with the dopamine receptor. Among the semirigid analogs of dopamine, the compounds with the greatest potency are those with the ethylamine side chain of dopamine in the fully extended form, as in apomorphine and 2-amino-6,7-dihydroxytetralin (12)(13)(14)(15)(16). On the other hand, there are significant differences indrugaffinity,subcellular localization, and ontogenetic developmental pattern between the dopamine receptor recognition site and adenylate cyclase (17)(18)(19)(20). Thus, the significance of the dopamine-sensitive adenylate cyclase data in relation to dopamine-mediated behaviors is not known.Apomorphine and 2-amino-6,7-dihydroxytetralin have an affinity for the dopamine receptor binding site as great or greater than that of dopamine (21). This affinity, however, may not be due to these compounds having the dopamine moiety in a fully extended form, because no binding study has been carried out comparing the affinity of isomeric compounds that possess a cis and trans relationship between the catechol and amino groups found in dopamine. Therefore, to determine the preferred conformation of dopamine at its receptor site, we Ci/mmol, New England Nuclear) which was added in 100 gl of 0.1% ascorbic acid, 1.8 ml of...

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.

Gemäß Formelbild wird das Isomere (VI) von Trimetoquinol (I) dargestellt.

Ausgehend von den Aldehyden (I) erhält man ‐über die Cyclobutanone (II) und Oxime (III) die Cyclobutylamine (IV) und (V), deren Hallucinogen‐ähnliche Wirkung be‐ 78 stimmt wird.

Piperonal (I) kondensiert mit dem S‐Ylid (II) zum Cyclobutanon (IIIa), dessen Oxim (IIIb) zu den isomeren Aminen (IVa) (katalytisch über Pt) bzw. (IVb) (Na/Isopropanol) reduziert werden kann.

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.

No abstract