Medetomidine analogs as selective agonists for the human α 2-adrenoceptors

Shilpa G. Lalchandani, Xiaoyang Zhang, Seoung Soo Hong, Stephen B. Liggett, Wei Li, Bob Moore, Duane Miller, Dennis R. Feller

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Abstract

α2-Adrenoceptor (AR) agonists have therapeutic applications in a variety of diseases. Medetomidine, an α2-AR agonist, belongs to 4-substituted imidazole class of compounds and is highly selective for the α2-AR. The benzylic methyl group of medetomidine and naphthalene imidazole was proposed to interact with rat brain α2-ARs via a methyl binding pocket in a manner analogous to its presence in α-methyl norepinephrine. A series of derivatives containing hydrophilic and hydrophobic substituents, as well as chiral and conformationally rigid analogs were used. In current binding and functional studies using human α2-AR subtypes expressed in Chinese hamster ovary cells, optimal interactions were observed with the presence of the methyl group on the benzylic carbon atom of naphthyl imidazole. Data obtained with various analogs have demonstrated that size, electronegativity, lipophilicity, chirality and conformational flexibility of the substituents at the carbon bridge of naphthyl imidazole are important factors for interaction of the imidazole class of ligands with these α2-AR subtypes. Taken collectively, the results obtained support the existence of the methyl binding pocket for optimal ligand receptor binding interactions in human α2-AR subtypes. Further, the results also suggest that, additional modifications of medetomidine and naphthyl methyl imidazole at the benzylic carbon atom, and/or on the aromatic and imidazole ring systems could provide insights into the chemical requirements for optimizing α 2-AR subtype selectivity. This could eventually lead to the discovery of promising compounds for the evaluation of the physiological importance of the three α2-AR subtypes.

Original languageEnglish (US)
Pages (from-to)87-96
Number of pages10
JournalBiochemical Pharmacology
Volume67
Issue number1
DOIs
StatePublished - Jan 1 2004

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Medetomidine
Adrenergic Receptors
Carbon
Ligands
Atoms
Electronegativity
Chirality
Cricetulus
imidazole
Cell Communication
Rats
Ovary
Brain
Norepinephrine
Cells
Derivatives

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

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Medetomidine analogs as selective agonists for the human α 2-adrenoceptors. / Lalchandani, Shilpa G.; Zhang, Xiaoyang; Hong, Seoung Soo; Liggett, Stephen B.; Li, Wei; Moore, Bob; Miller, Duane; Feller, Dennis R.

In: Biochemical Pharmacology, Vol. 67, No. 1, 01.01.2004, p. 87-96.

Research output: Contribution to journalArticle

Lalchandani, Shilpa G. ; Zhang, Xiaoyang ; Hong, Seoung Soo ; Liggett, Stephen B. ; Li, Wei ; Moore, Bob ; Miller, Duane ; Feller, Dennis R. / Medetomidine analogs as selective agonists for the human α 2-adrenoceptors. In: Biochemical Pharmacology. 2004 ; Vol. 67, No. 1. pp. 87-96.
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