A multireceptorial binding reinvestigation on an extended class of sigma ligands: N-[omega-(Indan-1-yl and tetralin-1-yl)alkyl] derivatives of 3,3-dimethylpiperidine reveal high affinities towards sigma(1) and EBP sites

New 1-[omega-(2,3-dihydro-1H-inden-1-yl)- and (2,3-dihydro-5-methoxy-1H-ind en-1-yl)alkyl and 1-[omega-(1,2,3,4-tetrahydronaphthalen-1-yl)- and (6-meth oxy- or 6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)aIkyl] derivatives of 3, 3-dimethylpiperidine were synthesized, as homologous compounds of an existi ng series of sigma ligands, in order to carry out sigma receptor subtypes s tructure-affinity relationships. The new compounds and some of their relate d analogues, already reported, were tested in new multi-receptorial radioli gand binding assays. As reference compounds, the known sigma (1) ligands SA 4503, ED 1008 and NE 100 were also prepared and tested. All reported compo unds showed high sigma (1) affinity assayed by (+)-[H-3]-pentazocine on gui nea-pig brain (apparent K-i = 1.75-72.2 nM) and moderate or low sigma (2) a ffinity by [H-3]-DTG on rat liver, in contrast with previous results. One t ertiary amine function spaced by a five-membered chain from a phenyl group is the structural feature shared by the most active compounds 26 and 43 and some reference al ligands. The reported ol ligands, including reference co mpounds, also demonstrated a high affinity towards EBP (Delta (8)-Delta (7) sterol isomerase) site (apparent K-i = 0.48-14.8 nM) and some of them (37 and 44) were good ligands at L-type Ca++ channel. 1-14-(2,3-Dihydro- 1H-ind en-1-yl)butyl]-3,3-dimethylpiperidine (26) was the best mixed sigma (1) and EBP ligand (apparent K-i = 1.75 and 1.54 nM, respectively) with a good sel ectivity versus sigma (2) receptor (138- and 157-fold, respectively). (C) 2 001 Elsevier Science Ltd. All rights reserved.