Novel potent sigma(1) ligands: N-[omega-(tetralin-1-yl)alkyl]piperidine derivatives

A series of substituted N-[(tetralin-1-yl)alkyl]piperidines and a number of related N-di-n-propyl[(tetralin-1-yl)alkyl]amines were prepared. Structural modifications such as piperidine substitutions, intermediate chain lengthening, and the nature of the aromatic ring were explored in order to identify structural requirements for selective al affinity. They were tested in radioligand binding assays on al, 5-HT1A and 5-HT2 serotonergic, PCP (phencyclidine), and D-2 dopaminergic receptors. Almost all the compounds reported here showed a high to superpotent sigma(1) affinity, and some compounds also demonstrated a widespread selectivity over the other receptors. In [H-3]-(+)-pentazocine binding, 3,3-dimethyl-1-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperidine (24) and 3,3-dimethyl-1-[4-(1,2,3,4-tetrahydronaphthalen-1-yl)-n-butyl]piperidine (26) reached the lowest K-i values (0.4 and 0.8 nM, respectively); compound 24 also demonstrated a considerable PCP affinity (K-i 34.2 nM), whereas compound 26 was suitably selective. Furthermore the presence of a 4-benzyl substituent on the piperidine ring (compound 16, K-i = 3.9 nM on sigma(1) sites) caused an increase in 5-HT1A affinity (K-i < 0.14 nM).