Structure-affinity relationships of a unique nicotinic ligand: N-1-dimethyl-N-4-phenylpiperazinium iodide (DMPP)

DMPP is a well-known nicotinic agonist that does not fit any proposed pharm acophore for nicotinic binding and represents a unique ligand among the hun dreds of nicotinic agonists studied in the past decades. A systematic modul ation of the chemical structure of DMPP, aimed to establish its structure-a ffinity relationships, is reported. The research has allowed to identify mo lecules such as I Ic, 13c, 14c, and 28c, with affinities for alpha (4)beta (2) receptors in the low nanomolar range, some 2 orders of magnitude lower than the lead compound. The agonistic properties of the most interesting co mpounds have been assessed by measuring their analgesic activity on mice (h ot-plate test). Another result of the research was the identification of DM PP analogues, such as 3a (K-i = 90 nM) and 14b (K-i = 180 nM), that maintai n affinity for the central nicotinic receptor when the ammonium function is changed into an aminic one and are therefore possible leads for drug devel opment in neurodegenerative diseases.