title: 4-(tetralin-1-yl)- and 4-(naphthalen-1-yl)alkyl derivatives of 1-cyclohexylpiperazine as sigma receptor ligands with agonist sigma2 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.
authors.affiliation: Dipartimento Farmacochimico, Università di Bari, via Orabona 4, I-70126 Bari, Italy. berardi@farmchim.uniba.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.forename: Savina
authors.initials: S
authors.lastname: Ferorelli
authors.forename: Carmen
authors.initials: C
authors.lastname: Abate
authors.forename: Nicola Antonio
authors.initials: NA
authors.lastname: Colabufo
authors.forename: Marialessandra
authors.initials: M
authors.lastname: Contino
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tortorella
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D009281:Naphthalenes; D017480:Receptors, sigma; D013764:Tetrahydronaphthalenes