Structure-activity studies of new imidazolines on adrenoceptors of rat aorta and human platelets

Summary

Potencies of new aromatic substituted fluoro or iodo analogues of catecholimidazolines on functional responses in rat aorta (α₁) and platelets (α₂) were quantified.

(1) When compared either on the basis of EC₅₀ or the dissociation constant (K_A), 5-fluorocatecholimidazoline was as potent as the reference α₁-adrenoceptor agonist, phenylephrine in the vascular tissue. The maximum contraction of aorta produced by the fluoro analogue was, however, 17% higher than that of phenylephrine. The time required for 1/2 relaxation of the tissue after 5-fluoro hydroxy imidazoline was at least twice as long as that of the phenylephrine. The catechol moiety as well as fluorine substitution at the critical 5-position of the aromatic ring is essential for higher α₁ adrenoceptor-mediated potency. (2) As compared to the fluoro analogues, the adrenoceptor-mediated potencies of iodo-analogues were relatively weak on vascular tissue. Naphazoline and its analogues were partial agonists on vascular tissue with dissociation constants which ranged from 110 to 2600 nmol/l. (3) Imidazole analogues were generally less potent agonist than the imidazolines by one order of magnitude. (4) The vascular effects of all agonists were competitively blocked by prazosin with K_B values which ranged from 0.04 to 0.48 nmol/l. Since the variation in K_B values were within normal limits, the action of new imidazolines on rat aorta appears to be mediated mainly by the activation of the α₁-adrenoceptor. Prazosin 10 nmol/l abolished the vascular response of some partial agonists. This indicates a slightly different mode of interaction of agonists with the transduction process. (5) Carbon 4-substituted imidazolines produced little or no α₁ adrenoceptor-mediated intrinsic activity, but competitive receptor blocking potency was comparable to that of phentolamine. (6) Medetomidine was a partial agonist on the rat aorta with a K_A of 260 nmol/l. When investigated as a blocker, the K_B of medetomidine against phenylephrine was approximately 5600 nmol/l. The variation in the latter value was high. (7) In acetylsalicylic acid-treated human platelets, the α₂-adrenoceptor-mediated aggregatory effect of all fluoro analogues was weak. lodo or naphazoline analogues did not initiate platelet aggregation but blocked the aggregation induced by epinephrine. The affinity of naphazoline for the α₂-adrenoceptor was 1100 nmol/l. The IC₅₀ of medetomidine for platelet anti-aggregatory effect was 3300 nmol/l, which compares favorably with other imidazoline type of blockes of platelet aggregation. (8) Sympathomimetic vasoconstrictor actions and platelet aggregation effects of these compounds can be dissociated. Some vasoconstrictors were antiaggregatory. The structure-activity relationships of the two receptor systems, namely rat aorta (α₁) and platelets (α₂), are discussed.