Synthesis and biological evaluation of 2-aryliminopyrrolidines as selective ligands for I1 imidazoline receptors: discovery of new sympatho-inhibitory hypotensive agents with potential beneficial effects in metabolic syndrome.

New 2-aryliminopyrrolidines (1-18) were synthesized and tested for their binding properties on I-1 imidazoline receptors vs a2-adrenergic receptors and their blood pressure effects after both systemic and intracerebral administrations. The purposes of this study were: (i) to analyze structureactivity and affinity relationships on I-1 imdazoline receptors and (ii) to propose some leader compounds for the development of new sympatho-inhibitory drugs with potential applications in hypertension and/or metabolic syndrome, i.e., a cluster of cardiovascular (hypertension) and metabolic disorders. Our study highlights decisive arguments of SAR concerning both the affinity for I(1)Rs and the hypotensive activity of 2-aryliminopyrrolidines. Binding assays showed high affinity and selectivity of some compounds for I-1 imidazoline receptors over alpha(2)-adreergic receptors. Compound 13 (laboratory reference LNP599; K-i = 3.2 nM on I(1)imidazoline receptors) is the prototype for the development of new centrally acting agents targeting specifically I(1)imidazoline receptors to be used in the management of hypertension and/or metabolic syndrome.