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Arzneimittelforschung 2006; 56(4): 269-275
DOI: 10.1055/s-0031-1296720
CNS-active Drugs · Hypnotics · Psychotropics · Sedatives
Editio Cantor Verlag Aulendorf (Germany)

Bioisosteric Modification of Salvinorin A, a Potent and Selective Kappa-Opioid Receptor Agonist

D. Jeremy Stewart
1   Department of Pharmacognosy and National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA
,
Hesham Fahmy
1   Department of Pharmacognosy and National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA
,
Bryan L. Roth
2   Departments of Biochemistry, Psychiatry and Neurosciences and Comprehensive Cancer Center and NIMH Psychoactive Drug Screening Program, Case Western Reserve University Medical School, Cleveland, Ohio, USA
,
Feng Yan
2   Departments of Biochemistry, Psychiatry and Neurosciences and Comprehensive Cancer Center and NIMH Psychoactive Drug Screening Program, Case Western Reserve University Medical School, Cleveland, Ohio, USA
,
Jordan K. Zjawiony
1   Department of Pharmacognosy and National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA
› Author Affiliations
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Publication History

Publication Date:
22 December 2011 (online)

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Summary

Salvinorin A ((2S,4aR,6aR,7R,9S,10aS, 10bR)-2H-naphtho[2,1-c]pyran-7-carboxylic acid, 9-(acetyloxy)-2-(3-furanyl) dodecahydro-6a,10b-dimethyl-4,10-dioxo methyl ester, 1, CAS 83729-01-5) has been shown to bind with high affinity and selectivity to the kappa-opioid receptor (KOR) as an agonist. Bioisosteres of 1 were developed and biologically evaluated in binding and functional assays. The C-2 thioacetate isoster produced comparable activity to 1, but nitrogen substitution had a diminishing effect. Intermediates, which lack a β-car-bonyl at C-2, displayed moderate affinity. The derivatives were tested against all opioid subtypes and were selective towards KOR.

Zusammenfassung

Bioisosterische Modifizierung von Salvinorin A, einem potenten und selektiven Kappa-Opioidrezeptor-Agonisten

Es wurde gezeigt, daβ Salvinorin A ((2S,4aR,6aR,7R,9S,10aS,10bR)-2H-Naphtho[2,1-c]pyran-7-carbonsäure, 9-(acetyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo methyl ester, 1, CAS 83729-01-5) als Agonist mit hoher Affinität und Selektivität an den Kappa-Opioidrezeptor (KOR) bindet. Die biologische Wirkung von Bioisosteren von 1 wurde in Bindungsund Funktionsassays evaluiert. Während im C-2-Thioazetat-Isoster eine vergleichbare Aktivität zu 1 gefunden wurde, war diese durch Stickstoffsubstitution vermindert. Intermediate, welchen ein Beta-Carbonyl an C-2 fehlt, zeigten mäβige Affinität. Die Derivate wurden gegen alle Opioid-Subtypen getestet und erwiesen sich als KOR-selektiv.

Key words

CAS 83729-01-5 - Kappa-opioid receptor agonist - Salvia divinorum - Salvinorin A