Synthesis and biological evaluation of pyrrolinic isosteres of rilmenidine. Discovery of cis-/trans-dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol-2-yl)-amine (LNP 509), an I1 imidazoline receptor selective ligand with hypotensive activity.

To find new compounds selective for purported I1 imidazoline receptors (I1Rs) over I2 imidazoline binding sites (I2BS) and alpha2-adrenoceptors (alpha2ARs), a series of pyrrolinic isosteres of rilmenidine has been prepared and their biological activity at I1Rs, I2BS, and alpha2ARs evaluated. This isosteric replacement provided us with compounds which still bound to I1Rs but not to I2BS nor to alpha2ARs. A limited structure-affinity relationship was generated around the heterocyclic moiety of these ligands. One compound in this series, LNP 509 (1e) [cis-/trans-dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol-2-yl)-amine], had no detectable affinity at alpha2ARs yet was capable of lowering blood pressure after central administration. These pyrrolinic analogues constitute a new chemical class of imidazoline related compounds with high selectivity for the I1Rs. They could be used as new tools in the study of I1Rs and in the conception of new centrally acting hypotensive drugs.