Medetomidine analogs as α2-adrenergic ligands. 2. Design, synthesis, and biological activity of conformationally restricted naphthalene derivatives of medetomidine

Xiaoyan Zhang, Xiao Tao Yao, James T. Dalton, Gamal Shams, Longping Lei, Popat N. Patil, Dennis R. Feller, Fu Lian Hsu, Cliff George, Duane Miller

Research output: Contribution to journalArticle

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Abstract

A new series of naphthalene analogs of medetomidine have been prepared and evaluated for their α-adrenergic activities. The methylnaphthyl analog 5a showed significant selectivity for α2-adrenoceptors and behaved as a partial α1-agonist in rat aorta preparations. In contrast, the Z-ethylene analog 8c was α1-selective and behaved as a potent α1-antagonist. Two rigid analogs (6 and 7) exhibited large differences in binding affinities at α1- vs α2-receptors, indicating that the conformational flexibility of 5a is important for the fulfillment of the α-adrenergic activities. Molecular modeling studies began with conformational analysis of classical phenethylamines and medetomidine analogs. Superimposition of medetomidine conformations with those of phenethylamines provided a tentative explanation for the α2-adrenergic activity of the new imidazoles. A common binding mode for phenethylamines and imidazoles with α2-adrenoceptors is proposed. Knowledge of the biological properties of the 4-substituted imidazoles, integrated with the information derived from computer-assisted molecular modeling, has provided new insights for the structural and conformational requirements of this class as new adrenergic drugs.

Original languageEnglish (US)
Pages (from-to)3001-3013
Number of pages13
JournalJournal of Medicinal Chemistry
Volume39
Issue number15
DOIs
StatePublished - Jul 19 1996

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Medetomidine
Imidazoles
Phenethylamines
Adrenergic Agents
Ligands
Adrenergic Receptors
Molecular Computers
Aorta
naphthalene

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Medetomidine analogs as α2-adrenergic ligands. 2. Design, synthesis, and biological activity of conformationally restricted naphthalene derivatives of medetomidine. / Zhang, Xiaoyan; Yao, Xiao Tao; Dalton, James T.; Shams, Gamal; Lei, Longping; Patil, Popat N.; Feller, Dennis R.; Hsu, Fu Lian; George, Cliff; Miller, Duane.

In: Journal of Medicinal Chemistry, Vol. 39, No. 15, 19.07.1996, p. 3001-3013.

Research output: Contribution to journalArticle

Zhang, Xiaoyan ; Yao, Xiao Tao ; Dalton, James T. ; Shams, Gamal ; Lei, Longping ; Patil, Popat N. ; Feller, Dennis R. ; Hsu, Fu Lian ; George, Cliff ; Miller, Duane. / Medetomidine analogs as α2-adrenergic ligands. 2. Design, synthesis, and biological activity of conformationally restricted naphthalene derivatives of medetomidine. In: Journal of Medicinal Chemistry. 1996 ; Vol. 39, No. 15. pp. 3001-3013.
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