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Titolo:
Stereochemical selectivity of methanandamides for the CB1 and CB2 cannabinoid receptors and their metabolic stability
Autore:
Goutopoulos, A; Fan, PS; Khanolkar, AD; Xie, XQ; Lin, SY; Makriyannis, A;
Indirizzi:
Univ Connecticut, Dept Pharmaceut Sci, Storrs, CT 06269 USA Univ Connecticut Storrs CT USA 06269 Pharmaceut Sci, Storrs, CT 06269 USA Univ Connecticut, Ctr Drug Discovery, Storrs, CT 06269 USA Univ Connecticut Storrs CT USA 06269 Drug Discovery, Storrs, CT 06269 USA Univ Connecticut, Dept Mol & Cell Biol, Storrs, CT 06269 USA Univ Connecticut Storrs CT USA 06269 ol & Cell Biol, Storrs, CT 06269 USA
Titolo Testata:
BIOORGANIC & MEDICINAL CHEMISTRY
fascicolo: 7, volume: 9, anno: 2001,
pagine: 1673 - 1684
SICI:
0968-0896(200107)9:7<1673:SSOMFT>2.0.ZU;2-X
Fonte:
ISI
Lingua:
ENG
Soggetto:
RAT-BRAIN; ANANDAMIDE AMIDOHYDROLASE; PHARMACOLOGICAL ACTIVITY; ASYMMETRIC-SYNTHESIS; IN-VIVO; ACID; ANALOGS; BINDING; AGONIST; LIGAND;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
52
Recensione:
Indirizzi per estratti:
Indirizzo: Makriyannis, A Univ Connecticut, Dept Pharmaceut Sci, Storrs, CT 06269 USAUniv Connecticut Storrs CT USA 06269 Storrs, CT 06269 USA
Citazione:
A. Goutopoulos et al., "Stereochemical selectivity of methanandamides for the CB1 and CB2 cannabinoid receptors and their metabolic stability", BIO MED CH, 9(7), 2001, pp. 1673-1684

Abstract

Several chiral, analogues of the endogenous cannabinoid receptor ligand, arachidonylethanolamide (anandamide)methylated at the 2,1' and 2' positions using asymmetric synthesis were evaluated in order to study (a) stereoselectivity of binding to CB1 and CB2 cannabinoid receptors, and (b) metabolic stability with regard to anandamide amidase. Enantiomerically pure 2-methyl arachidonic acids were synthesized through diastereoselective methylation of the respective chiral 2-oxazolidinone enolate derivatives and CBI and CB2receptor affinities of the resulting chiral anandamides were evaluated using a standard receptor binding assay. Introduction of a single 2-methyl group increased affinity for CBI, led to limited enantioselectivity and only modestly improved metabolic stability. However. a high degree of enantio- and diastereoselectivity was observed for the 2,1'-dimethyl analogues. (R)-N-(1- methyl-2-hydroxyethyl)-2-(R)-methyl-arachidonamide (4) exhibited the highest CB1 receptor affinity in this series with a K-i of 7.42 nM, an at least 10-fold improvement on anandamide (K-i = 78.2 nM), The introduction of two methyl groups at the 2-position of anandamide led to no change in affinity for CB1 but somewhat enhanced metabolic stability. Conversely, chiral headgroup methylation in the: 2-gem-dimethyl series led to chiral analogues possessing a wide range of CB1 affinities. Of these the (S)-2,2,2'-trimethylanalogue (12) had the highest affinity for CBI almost equal to that of anandamide. In agreement with our previous anandamide structure-activity relationship work, the analogues in this study showed high selectivity for the CBI receptor over CB2. The results are evaluated in terms of stereochemical factors affecting the ligands affinity for CB1 using receptor-essential volume mapping as an aid. Based on the results, a partial CBI receptor site model is proposed. that bears two hydrophobic pockets capable of accommodating 1'- and 2-methyl groups (C) 2001 Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 31/03/20 alle ore 17:21:15