Modelling of adrenoceptor ligand targets based on novel medium- or macro-sized fused nitrogen heterocyclic systems

Novel medium- and macro-sized heterocyclic compounds were assessed for thei r potential as subtype-selective adrenergic ligands, Their conformational f lexibilities were investigated and their geometric shapes were compared to rigid lead compounds of known selectivity. In the case of alpha(1A) selecti ve antagonists, interesting potential targets for synthesis and evaluation were identified by 'opening up' various rings of the fused-ring lead compou nd 1 by shared-bond cleavage. For alpha(2) selective ligands, compound 6 wa s the lead compound and the possibility of mimicking the fused-ring system via intramolecular hydrogen bonding was investigated. None of the potential targets were closely enough related in this case to the lead compound to w arrant synthesis.