4-(tetralin-1-yl)- and 4-(naphthalen-1-yl)alkyl derivatives of 1-cyclohexylpiperazine as σ receptor ligands with agonist σ2 activity

Several 1-cyclohexylpiperazine derivatives related to 92 receptor ligand 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (33, K-i = 0.34 nM) were synthesized and tested in radioligand binding assays, to attempt a structure-affinity relationship study. Intermediate alkyl chain length and methoxyl group position on the tetralin nucleus were varied. A few naphthalene analogues were also prepared. High affinities were found in sigma(2) receptor binding for almost all compounds, some of which displayed K-i values in subnanomolar range, but low sigma(2)/sigma(1) selectivities were found. The highest sigma(2) affinities were displayed by compounds with an intermediate alkyl chain of three (32 and 43) or five methylenes (39 and 46). Quite high sigma(1) receptor affinity was found for compounds with a four-methylene chain; 36 (K-i = 0.036 nM) and 45 (K-i = 0.22 nM) displaying good sigma(1)/sigma(2) selectivity (406- and 139-fold, respectively). Moreover, homologues of compound 33 displayed also satisfactory selectivities over dopamine D-2-like, serotonin 5-HT3, and adrenergic a, receptors. These compounds and a few others were tested in the inhibition of the electrically evoked contractions in guinea pig bladder and were demonstrated to be full sigma(2) agonists. The activity values correlated well to the affinity scale (EC50 in muM range). 33 and related compounds are proposed as a class of potential antineoplastic and PET diagnosis agents.