Summary
Adrenoceptor-mediated effects of the enantiomers of the optically active imidazoline, 2-(3,4,α-trihydroxybenzyl)imidazoline, and the corresponding desoxy derivative, 2-(3,4-dihydroxybenzyl)imidazoline, have been investigated in the pithed rat. The enantiomers and desoxy derivative were potent pressor agents with a direct action mediated predominantly via postsynaptic vascular α2-adrenoceptor. These compounds were significantly less potent at presynaptic α2-adrenoceptor in rat heart. The rank order of potency for the two enantiomers and desoxy derivative at postsynaptic vascular α1- and presynaptic cardiac α2-adrenoceptor in pithed rat were: desoxy≥R(−) >(+), consistent with our previous findings in vitro. This order of potency is not in agreement with the rank order of R(−)>S(+)=desoxy which is predicted by the Easson-Stedman Hypothesis. The β-adrenoceptor-mediated chronotropic and β-adrenoceptor-mediated vasodepressor effects of these imidazolines were also investigated in pithed rat and found to be weaker than either the α1- or α2-adrenoceptor-mediated effects. However, the rank order of potency of the enantiomers and corresponding desoxy derivative for β1- and β2-adrenoceptor-mediated effects was found to be similar to that order predicted by the Easson-Stedman Hypothesis. Studies with these optically active imidazoline enantiomers and corresponding desoxy derivativative indicate that quantitative as well as qualitative differences exist in the stereochemical requirements of α- and β-adrenoceptor. The results also support our previous observations which suggest that phenethylamines and imidazolines may interact differently with α-adrenoceptor since the former adhere strictly to the Easson-Stedman Hypothesis whereas the latter do not.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Beckett AH (1959) Stereochemical factors in biological activity. Fortschr Arzneimittelforsch 1:455–531
Blaschko H (1950) Remarks on chemical specificity. Proc Roy Soc (London B) 137:307–311
Bristow NW (1957) Mandelamidines as potential bronchodilators. J Chem Soc (Lond) Part 1:513–515
Broadley KJ (1982) Cardiac adrenoceptors. J Auton Pharmacol 2:119–145
Carlsson E, Ablad B, Brandstrom A, Carlsson B (1972) Differentiated blockade of the chronotropic effects of various adrenergic stimuli in the cat heart. Life Sci 11:953–958
Docherty JR, McGrath JC (1980) A comparison of pre- and postjunctional potencies of several α-adrenoceptor agonists in the cardiovascular system and anococcygeus muscle of the rat. Evidence for two types of postjunctional α-adrenoceptor agonists in the cardiovascular system and anococcygeus muscle of the rat. Evidence for two types of postjunctional α-adrenoceptor. Naunyn-Schmiedeberg's Arch Pharmacol 312:107–116
Easson LH, Stedman E (1933) CLXX. Studies on the relationship between chemical constitution and physiological action. V. Molecular dissymmetry and physiological activity. Biochem J 27: 1257–1266
Kaumann AJ (1981) In kitten ventricular myocardium, the inotropic potency of an agonist is determined by both its intrinsic activity for the adenylyl cyclase and its affinity for the β-adrenoceptor. Naunyn-Schmiedeberg's Arch Pharmacol 317:13–18
Kobinger W (1978) Central α-adrenergic systems as targets for hypotensive drugs. Rev Physiol Biochem Pharmacol 81:40–100
Kobinger W, Pichler L (1980) Investigation into different types of post-and presynaptic α-adrenoceptors at cardiovascular sites in rats. Eur J Pharmacol 65:393–402
Kobinger W, Lillie C, Pichler L (1980) Central cardiovascular α-adrenoceptors. Relation to peripheral receptors. Circ Res 46: (Suppl 1) I-21–I-26
Langer SZ, Massingham R, Shepperson N (1980) Presence of postsynaptic α2-adrenoceptors of predominantly extrasynaptic location in the vascular smooth muscle of the dog hind limb. Clin Sci (Oxford) 59:225s-228s
McGrath JC, Flavahan NA, McKean CE (1982) 226-2 and 226-3 mediated pressor and chronotropic effects in the rat and rabbit. J Cardiovasc Pharmacol 4:S101-S107
Miller DD, Hamada A, Rice PJ, Patil PN (1980) Optically active imidazolines and their interactions with α-adrenergic receptors. Abstr. of the Am. Chem. Soc., Div. of Med. Chem., abstr. no. 38
Miller DD, Patil PN, Feller DR (1982) Actions of stereoisomeric imidazolines on adrenergic tissues. Abstr. of the Am. Chem. Soc., Div. of Med. Chem., abstr. no. 5
Miller DD, hamada A, Craig EC, Christoph GG, Gallucci JC, Rice PJ, Banning JW, Patil PN (1983) Optically active catecholimidazolines: A study of their interaction with α-adrenoceptors. J Med Chem, in press
Mottram DR (1982) Differential activity of clonidine and α-methylnoradrenaline on α2-adrenoceptors. Br J Pharmacol 75: (suppl) 138P
Patil PN, LaPidus JB, Campbell D, Tye A (1967) Steric aspects of adrenergic drugs. II. Effects of d,l-isomers and desoxy derivatives on the reserpine pretreated rat vas deferens. J Pharmacol Exp Ther 155:13–23
Patil PN, Patel DG, Krell RD (1971) Steric aspects of adrenergic drugs. XV. Use of isomeric activity ratio as a criterion to differentiate adrenergic receptors. J Pharmacol Exp Ther 176:622–633
Patil PN, Miller DD, Trendelenburg U (1974) Molecular geometry and adrenergic drug activity. Pharmacol Rev 26:323–392
Portoghese PS (1970) Relationships between stereostructure and pharmacological activities. Ann Rev Pharmacol 10:51–76
Rice PJ, Hamada A, Miller DD, Patil PN (1982) α-Adrenoceptor stimulant activity of stereoisomeric catecholimidazolines and catecholimidates. Pharmacologist 24:222
Ruffolo RR, Jr (1983) Structure-activity relationships of α-adrenoceptor agonists. In: Kunos G (ed) Adrenoceptors and catecholamine action. Wiley-Interscience, New York, pp 1–50
Ruffolo RR Jr, Waddell JE (1982) Receptor interactions of imidazolines. IX. Cirazoline is an α1-adrenergic receptor agonist and an α2-adrenergic antagonist. J Pharmacol Exp Ther 222:29–36
Ruffolo RR Jr, Waddell JE (1983) Aromatic and benzylic hydroxyl substitution of imidazolines and phenethylamines: differences in activity at α1- and α2-adrenergic receptors. J Pharmacol Exp Ther 224:559–566
Ruffolo RR Jr, Turowski BS, Patil PN (1977) Lack of cross-desensitization between structurally dissimilar α-adrenoceptor agonists. J Pharm Pharmacol 29:378–380
Ruffolo RR Jr, Miller DD, Patil PN (1978) Some thoughts on the chemical and pharmacological aspects of adrenoreceptors. In: Szabadi E, Bradshaw CM, Bevan P (eds) Recent advances in the pharmacology of adrenoceptors. Elsevier/North Holland Biomedical Press, pp 45–50
Ruffolo RR Jr, Dillard RD, Yaden EL, Waddell JE (1979) Receptor interactions of imidazolines. II. Affinities and efficacies of hydroxysubstituted tolazoline derivatives in rat aorta. J Pharmacol Exp Ther 211:74–79
Ruffolo RR Jr, Yaden EL, Waddell JE, Dillard RD (1980) Receptor interactions of imidazolines. VI. Significance of carbon bridge separating phenyl and imidazoline rings of tolazoline-like α-adrenergic imidazolines. J Pharmacol Exp Ther 214:535–540
Ruffolo RR Jr, Yaden EL, Waddell JE (1982) Stereochemical requirements of α2-adrenoceptors receptors. J Pharmacol Exp Ther 222: 645–651
Ruffolo RR Jr, Rice PJ, Patil PN, Hamada A, Miller DD (1983) Differences in the applicability of the Easson-Stedman Hypothesis to the α1 and α2-adrenergic effects of phenethylamines and imidazolines. Eur J Pharmacol 86:471–475
Sanders J, Miller DD, Patil PN (1975) α-Adrenergic and histaminergic effects of tolazoline-like imidazolines. J Pharmacol Exp Ther 195:362–371
Sokal RA, Rohlf FJ (1969) Regression. In: Biochemistry, Freeman WH and Co., San Francisco, pp 404–493
Timmermans PBMWM, van Zwieten PA (1980) Vasoconstriction mediated by postsynaptic α2-adrenoceptors stimulation. Naunyn-Schmiedeberg's Arch Pharmacol 313:17–20
van Meel JCA, DeJonge A, Timmermans PBMWM, van Zwieten PA (1981) Selectivity of some α-adrenoceptor agonists for peripheral α1- and α2-adrenoceptors in the normotensive rat. J Pharmacol Exp Ther 219:760–767
Wilffert B, Timmermans PBMWM, van Zwieten PA (1982) Extrasynaptic location of α2- and noninnervated β2-adrenoceptors in the vascular system of the pithed normotensive rat. J Pharmacol Exp Ther 221:762–768
Woolf CM (1968) Principles of biometry: Statistics for biologists. van Nostrand, Princeton
Yamaguchi I, Kopin IJ (1980) Differential inhibition of α1- and α2-adrenoceptor mediated pressor responses in pithed rats. J Pharmacol Exp Ther 214:275–281
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ruffolo, R.R., Patil, P.N. & Miller, D.D. Adrenoceptor-mediated effects of optically active catecholimidazolines in pithed rat. Naunyn-Schmiedeberg's Arch. Pharmacol. 323, 221–227 (1983). https://doi.org/10.1007/BF00497667
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00497667