Several 1-cyclohexylpiperazine derivatives related to ó2 receptor ligand 1-cyclohexyl-4-[3-(5- methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (33, Ki ) 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 ó2 receptor binding for almost all compounds, some of which displayed Ki values in subnanomolar range, but low ó2/ó1 selectivities were found. The highest ó2 affinities were displayed by compounds with an intermediate alkyl chain of three (32 and 43) or five methylenes (39 and 46). Quite high ó1 receptor affinity was found for compounds with a four-methylene chain; 36 (Ki ) 0.036 nM) and 45 (Ki ) 0.22 nM) displaying good ó1/ó2 selectivity (406- and 139-fold, respectively). Moreover, homologues of compound 33 displayed also satisfactory selectivities over dopamine D2-like, serotonin 5-HT3, and adrenergic R1 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 ó2 agonists. The activity values correlated well to the affinity scale (EC50 in íM range). 33 and related compounds are proposed as a class of potential antineoplastic and PET diagnosis agents.

4-(Tetralin-1-yl)- and 4-(Naphthalen-1-yl)alkyl Derivatives of 1-Cycloheylpiperazine as sigma receptor Ligands with Agonist sigma 2 Activity

BERARDI, Francesco;FERORELLI, Savina;ABATE, CARMEN rosa;CONTINO, MARIALESSANDRA;PERRONE, Roberto;
2004

Abstract

Several 1-cyclohexylpiperazine derivatives related to ó2 receptor ligand 1-cyclohexyl-4-[3-(5- methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (33, Ki ) 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 ó2 receptor binding for almost all compounds, some of which displayed Ki values in subnanomolar range, but low ó2/ó1 selectivities were found. The highest ó2 affinities were displayed by compounds with an intermediate alkyl chain of three (32 and 43) or five methylenes (39 and 46). Quite high ó1 receptor affinity was found for compounds with a four-methylene chain; 36 (Ki ) 0.036 nM) and 45 (Ki ) 0.22 nM) displaying good ó1/ó2 selectivity (406- and 139-fold, respectively). Moreover, homologues of compound 33 displayed also satisfactory selectivities over dopamine D2-like, serotonin 5-HT3, and adrenergic R1 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 ó2 agonists. The activity values correlated well to the affinity scale (EC50 in íM range). 33 and related compounds are proposed as a class of potential antineoplastic and PET diagnosis agents.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11586/129826
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