4-(Tetralin-1-yl)- and 4-(Naphthalen-1-yl)alkyl Derivatives of 1-Cyclohexylpiperazine as σ Receptor Ligands with Agonist σ₂ Activity

Abstract

Several 1-cyclohexylpiperazine derivatives related to sigma(2) 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-HT(3), and adrenergic alpha(1) 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 (EC(50) in microM range). 33 and related compounds are proposed as a class of potential antineoplastic and PET diagnosis agents.

<![CDATA[Binding characteristics of sigma2 receptor ligands]]>

“…Berardi et al, 1998;Berardi et al, 2004;Fujimura et al, 1997;Kawamura et al, 2003;Mach et al, 2004;Maeda et al, 2002;Maier and Wunsch, 2002;Marrazzo et al, 2001;Matsumoto et al, 2004). Of particular interest is a series of substituted tetralins bearing a gem-dimethyl piperidine.…”

1‐Cyclohexyl‐4‐(4‐arylcyclohexyl)piperazines: Mixed σ and Human Δ8–Δ7 Sterol Isomerase Ligands with Antiproliferative and P‐Glycoprotein Inhibitory Activity

“…[14,15] The mechanism through which s receptors induce apoptosis is not yet understood, because contradictory results were obtained for different cells and/or different ligands. [16][17][18][19][20] Studies…”

Synthesis and Structure−Activity Relationships of 1-Aralkyl-4-Benzylpiperidine and 1-Aralkyl-4-Benzylpiperazine Derivatives as Potent σ Ligands

“…Moreover, a methoxy group was inserted on the available positions of the aromatic moiety (Ar in the General formula A, Chart 2) in order to test the space around it; this substitution could be of great interest, since a strong effect depending on the position of a methoxy group was observed in a series of (tetralinopropyl)piperazines σ ligands. 15 In addition, we synthesized and tested a series of piperazine derivatives of general formula B (Chart 2), to compare their affinity with that of the corresponding piperidines.…”