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 I-1 imidazoline receptor selective ligand with hypotensive activity

To find new compounds selective for purported I-1 imidazoline receptors (I( 1)Rs) over I-2 imidazoline binding sites (I2BS) and alpha (2)-adrenoceptors (alpha (2)ARs), a series of pyrrolinic isosteres of rilmenidine has been p repared and their biological activity at I(1)Rs, I2BS, and alpha (2)ARs eva luated. This isosteric replacement provided us with compounds which still b ound to I(1)Rs but not to I2BS nor to alpha (2)-ARs. A limited structure-af finity relationship was generated around the heterocyclic moiety of these l igands. One compound in this series, LNP 509 (1e) [cis-/trans-dicyclopropyl methyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol-2-yl-amine], had no detectable a ffinity at alpha (2)ARs yet was capable of lowering blood pressure after ce ntral administration. These pyrrolinic analogues constitute a new chemical class of imidazoline related compounds with high selectivity for the I(1)Rs . They could be used as new tools in the study of I(1)Rs and in the concept ion of new centrally acting hypotensive drugs.