α2-Adrenoceptor agonist properties of exo- and endo-isomers of 2-amino-6,7,dihydroxybenzo-norbornene designed as rigid catecholamines

Abstract

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.

Medetomidine Analogs as α2-Adrenergic Ligands. 2. Design, Synthesis, and Biological Activity of Conformationally Restricted Naphthalene Derivatives of Medetomidine

“…One of the most frequently used methods is to design conformationally restricted analogs derived from a flexible molecule. Such a method has been successfully carried out to study the conformation−activity relationships of the phenethylamine class. − The present report includes two novel conformationally restricted analogs of 5a which incorporate the benzylic methyl group at either the 8-position (compound 6 ) or 2-position (compound 7 ) of the naphthyl ring (Figure ). The major drawback of this design is that in order to construct these rigid molecules, additional atoms and bonds have to be added to the parent compound ( 5a ) which could potentially affect the chemical and physical properties of the drug, particularly its hydrophilic properties in this case.…”

α‐adrenoceptors: Recent developments

“…168 It was observed that the endo-isomer, which corresponded to the cis-folded conformation of a phenethylamine, was inactive at both al-and a,-adrenoceptors, in contrast to the exoisomer, which corresponded to the trans-extended conformation, which was extremely potent at both al-and a,-adrenoceptors. These results are consistent with those described above which indicate that for activation of both al-and a,-adrenoceptors, a fully extended-trans conformation of a phenethylamine is required.…”

Spirotetrahydronaphthalene analogues of sympathomimetic catecholamines. Synthesis and adrenergic activity of 5,6- and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1(2H)-3′ -piperidines]

“…The synthesis and the study of pharmacological properties of rigid or semi-rigid analogues of drugs possessing a conformational freedom represent one of the most eOE ective methods to obtain information on the spatial arrangement of pharmacophores (Smissman et al 1971;Nishikawa et al 1975;De Marinis et al 1982;RuOE olo et al 1982;Hicks et al 1983;De Bernardis et al 1985, 1986Kumar et al 1987;Balsamo et al 1989;Macchia et al 1992Macchia et al , 1993Macchia et al , 1995Macchia et al , 1997Cannon 1995). The adrenergic catecholamine aminoalcohols of type 1 and drugs structurally related to them are molecules which, with a simple rotation around the single bonds C a >C 1 , C 1 >C 2 , C 2 >N, may assume diOE erent low-energy conformations, in which the moieties presumed to be responsible for biological activity (alcoholic hydroxy group, amino nitrogen, catecholic group) can interact with the receptor (Easson & Stedman 1933;Ariens 1967;Brittain et al 1970;Petrongolo et al 1974;Triggle 1981).…”