Synthesis and pharmacological evaluation of potent and enantioselective sigma 1, and sigma 2 ligands.
In a previous study we found that substitutions of the (+)-cis-N-normetazocine nucleus of (+)-MPCB with 1-adamantanamine provide the compound (+/-)-10 with high affinity and selectivity for sigma receptors. Starting with this result we have synthesized a new series of eight 1-phenyl-2-cyclopropylmethylamines structurally related to (+/-)-10, and binding affinities, with respect to sigma 1, sigma 2, opioid and dopaminergic D2 receptors, have been reported. All compounds showed a negligible opioid and dopaminergic affinity and high selectivity for sigma receptors. Modifications on the amino moiety and methylcarboxyester group of 10 provide compounds with different sigma 1 and sigma 2 binding affinity and selectivity. Moreover, we have also synthesized the respective enantiomers of componds (+/-)-10 and (+/-)-18 in order to evaluate the enantioselectivity for sigma 1 and sigma 2 receptors. The binding data showed that carboxymethylester on the cyclopropane ring was more critical for enantioselectivity than the hydroxymethylenic group. In fact, the (-)-10 enantiomer showed a preference for sigma 1 whereas (+)-10 showed a preference for sigma 2.
Marrazzo
A
A
Department of Pharmaceutical Sciences, University of Catania, Viale Andrea Doria 6, 95125 Catania, Italy.
Prezzavento
O
O
Pasquinucci
L
L
Vittorio
F
F
Ronsisvalle
G
G
D000595:Amino Acid Sequence; D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000494:pharmacology*; D003496:Cyclazocine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D017480:Receptors, sigma / Q000187:drug effects*; D013237:Stereoisomerism; D000097605:Sigma-1 Receptor
D000701:Analgesics, Opioid; D003496:Cyclazocine; D008024:Ligands; D017448:Receptors, Dopamine D2; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C110285:6,11-dimethyl-1,2,3,4,5,6-hexahydro-3-((2'-(methoxycarbonyl)-2'-phenylcyclopropyl)methyl)-2,6-methano-3-benzazocin-8-ol; C106107:sigma-2 receptor; C014716:normetazocine