Pharmacological characterization of selected agonists and antagonists on human alpha-adrenergic receptor subtypes

Alpha-adrenoceptors (ARs) represent a distinct family of G-protein coupled receptors that respond to the endogenous catecholamines, norepinephrine and epinephrine and mediate control of many physiological responses on the central and autonomic nervous system. They represent a distinct family of G-protein coupled receptors and has been subdivided into three subtypes: alpha-2A, alpha-2B and alpha-2C. The lack of subtype selective drugs has precluded the clarification of the role of each alpha2-AR subtype and has limited the therapeutic utility of agents acting on these receptors.;We have been able to identify alpha-2 selective agonists based on our hypothesis that this class of receptors possesses an additional pocket to accommodate a methyl group. This pocket is not present in the other adrenergic receptors. We have also been able to develop selective antagonists for the alpha-2C adrenergic subtype using dimeric analogs. Our dimeric analogs are the most selective antagonists identified so far for the alpha2C-adrenoceptor subtype. Our selective antagonists will be an important tool in understanding the role of this adrenergic subtype and could have important therapeutic applications.;We have also determined the effect of temperature on the alpha-2A and alpha-2C AR subtypes to determine the potential role of these subtypes in cold-induced vasoconstriction observed in conditions such as Raynaud's disease. Our results show a change in G-protein coupling as well as receptor density for the alpha-2A receptors subjected to lowered temperature. Our results suggest that the alpha-2C receptors could be responsible for the cold-induced vasoconstriction in conditions such as Raynaud's disease. Therefore, selective alpha-2C antagonists identified in our study could be used in the treatment of vascular disease such as Raynaud's disease.