A series of N-substituted exo- and endo-isomers of 2-amino-6,7-dihydroxybenzonorbornene, designed as rigid catecholamines, have been studied in the pithed rat in-vivo, as vasoconstrictor agents, and as inhibitors of the twitch response in the transmurally stimulated guinea-pig ileum. The exo-isomers examined were vasoconstrictor agonists in the pithed rat and inhibited the twitch response of the ileum. The corresponding endo-isomers were inactive in both preparations. The exo-isomers were less potent than the alpha 2-receptor agonist TL99, but were all directly acting vasoconstrictor agents, since they were still effective in reserpine-pretreated animals. Responses induced by members of the exo-series were selectively antagonized by the alpha 2-receptor antagonist rauwolscine, but were not antagonized by the alpha 1-receptor antagonist, prazosin, or the dopamine-receptor antagonist alpha-flupenthixol. The results demonstrate important conformational requirements for the interaction of catecholamines at presynaptic or postsynaptic alpha 2-receptors, and suggest that a fully extended or anti-conformation of the noradrenaline molecule is involved in alpha 2-receptor-agonist interaction.

Stereospecific syntheses of exo-2-amino-5,6-dihydroxybenzonorbornene (11f), exo-2-amino-6,7-dihydroxybenzonorbornene (11h), exo-2-amino-7,8-dihydroxybenzonorbornene (11g), and endo-2-amino-6,7-dihydroxybenzonorbornene (14d), rigid analogues of dopamine, are described. Compounds 11 h and 14d, their N-methyl (11i and 11j) and N,N-dimethyl (14i and 14j) derivatives, and compounds 11f and 11g were inactive as dopamine agonists when evaluated for dopaminergic activity by their ability to induce stereotyped behavior in mice after subcutaneous injection and by their ability to cause hyperactivity in rats after bilateral injection into the nucleus accumbens. However, compounds 11f, 11g, 11h, and the N-methyl derivatives 11i and 14d were all effective in displacing [3H]-2-amino-6,7-dihydroxytetralin ([3H]ADTN) and [3h[-N-n-propylnorapomorphine ([3H]NPA) from rat striatal membranes.

and Pharmacy", U n i v e r s i t y o f Manchester, Manchester M13 9PT U.K. B r a i n c o n c e n t r a t i o n s o f 5-hydroxytryptamine a r e i m p o r t a n t i n t h e a n a l g e s i c a c t i o n s o f o p i a t e s and sympathomimetics, b u t n o t i n t h a t o f c h o l i n o m i m e t i c s (Major & P l e u v r y 1970; P l e u v r y 6 Tobias 1971). Some o f amphetamine's u n d e s i r a b l e a c t i o n s ( n o t a b l y e x c i t a t i o n ) can be reduced by r e n d e r i n g t h e molecule s t e r e o c h e m i c a l l y more r i g i d , and we have r e c e n t l y r e p o r t e d t h e a c t i v i t i e s o f two c o n t r a s t i n g r i g i d amphetamine d e r i v a t i v e s , t h e and eisomers o f 2-aminobenzonorbornene and t h e i r N-methyl d e r i v a t i v e s (Burn e t a l 1980).

The carbon-13 N M R spectra of a series of exeand endo-ephers of 2-substituted benzonorbornene (Z-subtituent = OH, OCHO, Br, NH,, NHMe or NMed have been examined. The spectra are readily assigned by comparison with the coupled and off-resonance proton decoupled spectra as well as by the use of shift reagents. Interesting and diagnostic features of the spectra allow the distinction between ephers.

Das Cyclopentadiencycloaddukt (I) wird zur Verbindung (II) methyliert, aus der man die Amine (III) und (IV) erhält.