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 numb er of related N-di-n-propyl[(tetralin-1-yl)alkyl]amines were prepared. Structural modifications such as piperidine substitutions, intermedia te chain lengthening, and the nature of the aromatic ring were explore d in order to identify structural requirements for selective al affini ty. 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 s electivity over the other receptors. In [H-3]-(+)-pentazocine binding, 3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperidine (24) and ,3,4-tetr ahydronaphthalen-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 suit ably selective. Furthermore the presence of a 4-benzyl substituent on the piperidine ring (compound 16, K-i = 3.9 nM on sigma(1) sites) caus ed an increase in 5-HT1A affinity (K-i < 0.14 nM).