Ligand design for alpha(1) adrenoceptors.
An area of continuing interest in medicinal chemistry is the design, synthesis and pharmacological evaluation of ligands which bind at adrenoceptor subtypes, which include alpha(1A), alpha(1B), alpha(1D); alpha(2A), alpha(2B), alpha(2C); beta(1), beta(2), beta(3) and possibly beta(4) subtypes. The selective blockade or stimulation of these receptor subtypes is of on-going pharmacological and medicinal interest. However, the design principles for ligand differentiation at these subtypes still need further development. This review focuses on alpha(1) adrenoceptors with a concentration on literature over the past five years. Structural, physiological and therapeutic aspects of the alpha(1A), alpha(1B) and alpha(1D) subtypes are discussed together with ligands binding to these receptor subtypes. Approaches to alpha(1) adrenoceptor ligand design based on known ligands and on receptor docking are evaluated. A new combined approach using pharmacophores and receptor docking affords possibilities for deeper insights into achieving small molecule binding selectivity.
Department of Chemistry, University of Wollongong, Wollongong, NSW, 2522, Australia. john_bremner@uow.edu.au
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Bremner
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Griffith
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Coban
D000316:Adrenergic alpha-Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000595:Amino Acid Sequence; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry / Q000145:classification / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D008024:Ligands; D018340:Receptors, Adrenergic, alpha-1