Medetomidine analogs as α2-adrenergic ligands. 3. Synthesis and biological evaluation of a new series of medetomidine analogs and their potential binding interactions with α2-adrenoceptors involving a 'methyl pocket'

Xiaoyan Zhang, Joseph E. De Los Angeles, Mei Ying He, James T. Dalton, Gamal Shams, Longping Lei, Popat N. Patil, Dennis R. Feller, Duane Miller, Fu Lian Hsu

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The synthesis and the biological evaluation of a new series of medetomidine analogs are reported. The substitution pattern at the phenyl ring of the tetralin analogs had a distinct influence on the α2- adrenoceptor binding affinity. 4-Methylindan analog 6 was the most potent α2-adrenoceptor binding ligand among these 4-substituted imidazoles, and its α2-adrenoceptor selectivity was greater than the 5-methyl tetralin analog 4c. Ligand-pharmacophore and receptor modeling were combined to rationalize α2-adrenoceptor binding data of the imidazole analogs in terms of ligand-receptor interactions. The structure-activity relationships that were apparent from this and previous studies were qualitatively rationalized by the binding site models of the α2-adrenoceptor. The benzylic methyl group of medetomidine or the naphthyl analog 2a was superimposable with the α-methyl group of (-)-α-methylnorepinephrine and fit into the proposed 'methyl pocket' of the α2-adrenoceptor defined by the residues Leu110, Leu169, Phe391, and Thr395.

Original languageEnglish (US)
Pages (from-to)3014-3024
Number of pages11
JournalJournal of Medicinal Chemistry
Volume40
Issue number19
DOIs
StatePublished - Sep 26 1997

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Medetomidine
Adrenergic Agents
Adrenergic Receptors
Ligands
Nordefrin
Imidazoles
Structure-Activity Relationship
Binding Sites

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Medetomidine analogs as α2-adrenergic ligands. 3. Synthesis and biological evaluation of a new series of medetomidine analogs and their potential binding interactions with α2-adrenoceptors involving a 'methyl pocket'. / Zhang, Xiaoyan; De Los Angeles, Joseph E.; He, Mei Ying; Dalton, James T.; Shams, Gamal; Lei, Longping; Patil, Popat N.; Feller, Dennis R.; Miller, Duane; Hsu, Fu Lian.

In: Journal of Medicinal Chemistry, Vol. 40, No. 19, 26.09.1997, p. 3014-3024.

Research output: Contribution to journalArticle

Zhang, Xiaoyan ; De Los Angeles, Joseph E. ; He, Mei Ying ; Dalton, James T. ; Shams, Gamal ; Lei, Longping ; Patil, Popat N. ; Feller, Dennis R. ; Miller, Duane ; Hsu, Fu Lian. / Medetomidine analogs as α2-adrenergic ligands. 3. Synthesis and biological evaluation of a new series of medetomidine analogs and their potential binding interactions with α2-adrenoceptors involving a 'methyl pocket'. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 19. pp. 3014-3024.
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