Synthesis and α2-Adrenoceptor Effects of Substituted Catecholimidazoline and Catecholimidazole Analogs in Human Platelets

Duane Miller, Akihiko Hamada, Michael T. Clark, Adeboye Adejare, Popat N. Patil, Gamal Shams, Karl J. Romstedt, Sung U. Kim, Urusa Intrasuksri, Jacqueline L. McKenzie, Dennis R. Feller

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

It is known that the steric requirements for the interactions of catecholamines and catecholimidazolines with α1and α2-adrenoceptors are different. New analogues of desoxycatecholimidazoline (1), desoxycatecholimidazole (3), benzylic hydroxyl substituted imidazole (4), and the aromatic fluorine substitution analogues of 1 at the 2 (5), 5 (6), and 6 (7) positions, and a set of asymmetric 4-substituted catecholimidazolines, S-8 and R-8, were prepared and tested for interaction with α2-adrenoceptors in human platelets. With the exception of 3, all compounds were selective for α-adrenoceptor-mediated responses in human platelets. Introduction of a double bond in imidazoline 1 to give an imidazole 3 or the introduction of a benzylic hydroxyl group to 3, as in 4, reduced the inhibition of platelet aggregation with a rank order potency of 1 <3 <4. Fluorine atom substitution at the 2-, 5-, or 6-positions only slightly modified the inhibitory activity of 1. Each analogue (1,3-7) produced α2-mediated inhibition of platelet adenylate cyclase and can be classified as a partial agonist. The inhibition potency of S-8 and R-8 against epinephrine-induced aggregatory responses were greatly different, and only R-8 and 4 were α2-agonists on human platelet function. Our studies provide further evidence for the differential interaction of catecholamines and catecholimidazolines in α1- and α2-adrenoceptor systems.

Original languageEnglish (US)
Pages (from-to)1138-1144
Number of pages7
JournalJournal of Medicinal Chemistry
Volume33
Issue number4
DOIs
StatePublished - Jan 1 1990
Externally publishedYes

Fingerprint

Adrenergic Receptors
Blood Platelets
Fluorine
Hydroxyl Radical
Catecholamines
Imidazolines
Platelet Aggregation
Adenylyl Cyclases
Epinephrine
S(8)
imidazole

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and α2-Adrenoceptor Effects of Substituted Catecholimidazoline and Catecholimidazole Analogs in Human Platelets. / Miller, Duane; Hamada, Akihiko; Clark, Michael T.; Adejare, Adeboye; Patil, Popat N.; Shams, Gamal; Romstedt, Karl J.; Kim, Sung U.; Intrasuksri, Urusa; McKenzie, Jacqueline L.; Feller, Dennis R.

In: Journal of Medicinal Chemistry, Vol. 33, No. 4, 01.01.1990, p. 1138-1144.

Research output: Contribution to journalArticle

Miller, D, Hamada, A, Clark, MT, Adejare, A, Patil, PN, Shams, G, Romstedt, KJ, Kim, SU, Intrasuksri, U, McKenzie, JL & Feller, DR 1990, 'Synthesis and α2-Adrenoceptor Effects of Substituted Catecholimidazoline and Catecholimidazole Analogs in Human Platelets', Journal of Medicinal Chemistry, vol. 33, no. 4, pp. 1138-1144. https://doi.org/10.1021/jm00166a009
Miller, Duane ; Hamada, Akihiko ; Clark, Michael T. ; Adejare, Adeboye ; Patil, Popat N. ; Shams, Gamal ; Romstedt, Karl J. ; Kim, Sung U. ; Intrasuksri, Urusa ; McKenzie, Jacqueline L. ; Feller, Dennis R. / Synthesis and α2-Adrenoceptor Effects of Substituted Catecholimidazoline and Catecholimidazole Analogs in Human Platelets. In: Journal of Medicinal Chemistry. 1990 ; Vol. 33, No. 4. pp. 1138-1144.
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AU - Adejare, Adeboye

AU - Patil, Popat N.

AU - Shams, Gamal

AU - Romstedt, Karl J.

AU - Kim, Sung U.

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AU - McKenzie, Jacqueline L.

AU - Feller, Dennis R.

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