IMIDAZOLINES AS PROBES OF IGRS AND ALPHA-ADRENOCEPTORS

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The binding of catecholamines and 2-substituted imidazolines may have a common interaction of the charged amine and imidazoline functions, respectively, with the Asp-113 residue of the alpha-adrenoceptor, and the remaining functional groups of two chemical classes of agonists interact differently with other regions of the alpha-adrenoceptor. There are configurational and conformational requirements at ligand binding sites which are unique to catecholamines and 2-substituted imidazolines. The isothiocyanato imidazoline analog, IBI, was characterized as an agonist of a non-alpha-adrenergic receptor system in blood vessels which may be identical to one of the proposed subtypes of imidazoline-guanidinium receptor sites (IGRS). The aims of this proposal are to synthesis new 4-substituted imidazoline and IBI-related analogs to elucidate the specific molecular requirements for activation of alpha1- and alpha2-adrenergic receptors, and IGRS, respectively. Chemical objectives include the synthesis of a series of optically active and conformationally restricted set of 4-substituted imidazoline analogs along with a set of homologs to gain a better understanding of the structural, including stereochemical, requirements for both affinity and intrinsic activity of alpha-adrenergic receptors; and a series of affinity and photoaffinity labels of IBI, cirazoline and idazoxen molecules to probe the structural requirements for both stimulant or blocking properties, and to determine the pharmacologic relationship of this IBI - sensitive receptor to IGRS. Pharmacological objectives include quantification of alpha1 - and alpha2-adrenergic mediated activity in aortic tissue (alpha1-), vas deferens (prejunctional alpha2-and postjunctional alpha1-), platelets (alpha2A-) and hepatocytes (alpha1-) to evaluate the potency of 4-substituted imidazolines IBI analogs; characterization of the molecular mechanism of action of IBI and imidazoline affinity labels on IGRS in selected tissues (aorta, brain, platelets and adipocytes); investigation of the competitive interaction of imidazolines using radioligands for IGRS and alpha1-alpha2-adrenergic systems; and examination of the in vitro observations. These investigations will provide therapeutic insights into the possible development of new drugs that may be useful for the treatment of CNS disorders, nasal and ocular congestion, glaucoma, liver cell degenerative diseases, diarrhea and hypertension in humans.