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-cyclopropylmet...

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Published inFarmaco (Società chimica italiana : 1989) Vol. 56; no. 3; pp. 181 - 189
Main Authors Marrazzo, A, Prezzavento, O, Pasquinucci, L, Vittorio, F, Ronsisvalle, G
Format Journal Article
LanguageEnglish
Published LAUSANNE Elsevier 01.03.2001
Subjects
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
sigma receptors
ligands
stereoselectivity
CLONING
OPIOID RECEPTORS
RAT-BRAIN
BINDING-SITES
EXPRESSION
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Summary: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 D-2 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 enantionter showed a preference for sigma(1) whereas (+)-10 showed a preference for sigma(2), (C) 2001 Elsevier Science S.A. All rights reserved.
ISSN:0014-827X
DOI:10.1016/S0014-827X(01)01039-4