Salvinorin A, an Active Component of the Hallucinogenic SageSalvia divinorumIs a Highly Efficacious κ-Opioid Receptor Agonist: Structural and Functional Considerations

Abstract

The diterpene salvinorin A from Salvia divinorum has recently been reported to be a high-affinity and selective -opioid receptor agonist (Roth et al., 2002). Salvinorin A and selected derivatives were found to be potent and efficacious agonists in several measures of agonist activity using cloned human -opioid receptors expressed in human embryonic kidney-293 cells. Thus, salvinorin A, salvinorinyl-2-propionate, and salvinorinyl-2-heptanoate were found to be either full (salvinorin A) or partial (2-propionate, 2-heptanoate) agonists for inhibition of forskolinstimulated cAMP production. Additional studies of agonist potency and efficacy of salvinorin A, performed by cotransfecting either the chimeric G proteins Gaq-i5 or the universal G protein Ga16 and quantification of agonist-evoked intracellular calcium mobilization, affirmed that salvinorin A was a potent and effective -opioid agonist. Results from structure-function studies suggested that the nature of the substituent at the 2-position of salvinorin A was critical for -opioid receptor binding and activation. Because issues of receptor reserve complicate estimates of agonist efficacy and potency, we also examined the agonist actions of salvinorin A by measuring potassium conductance through G protein-gated K ϩ channels coexpressed in Xenopus oocytes, a system in which receptor reserve is minimal. Salvinorin A was found to be a full agonist, being significantly more efficacious than (trans)-

Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies

“…After an overnight serum depriva-tion, intracellular calcium flux assays were performed using a Molecular Devices Calcium Plus Assay kit and a FLEX Station II fluorescence plate reader (Molecular Devices). 46,47 with a few modifications. Briefly, cells were washed once with 100 ml serum-free, indicator-free DMEM.…”

Salvia divinorum Epling & Játiva (Maria Pastora) e Salvinorina A: crescente uso recreacional e potencial de abuso

“…A planta Salvia divinorum (SDI), da família Lamiaceae, tem sido usada por séculos pela cultura mazateca (Wolowich et al, 2006) e vem ganhando popularidade como droga recreacional nos últimos anos (Chavkin et al, 2004;Grundmann et al, 2007). É uma erva perene, natural da serra mazateca de Oxaca, no México (Vortherms & Roth, 2006;Valdes, 1994).…”

“…O diterpeno SA, agonista kappa opióide de alta afinidade (Chavkin et al, 2004;Roth et al, 2002), tem potencial psicotrópico similar ao da mescalina (Giroud et al, 2000), porém com diferentes efeitos (Braida et al, 2007). Tem baixa biodisponibilidade oral, o que motivou a pesquisa de análogos como a N-metilacetamida (Béguin et al, 2007).…”

“…SA e outros agonist as kappa-opi ói des diminuem significativamente os níveis basais de dopamina, assim como impedem o aumento dos níveis dopaminérgicos (Prisinzano et al, 2005). Pesquisa-se o uso de agonistas seletivos de KOP no tratamento da dependência por estimulantes (Prisinzano et al, 2005;Chefer et al, 2005). Parece também atuar como eficiente bloqueador do efeito de recompensa provocado por morfina (Narita et al, 2005), levando em conta que o KOP participa da expressão da síndrome de abstinência crônica induzida por aquele opióide (Lee et al, 2005).…”

Studies Towards the Synthesis of Salvinorin A

“…[2,4] Extensive receptor assays have indicated that salvinorin A acts selectively as a potent κ-opioid receptor (KOR) agonist [5,6] exhibiting similar efficacy to known KOR agonists U69,593 and TRK-820. [7] The biological properties of salvinorin A are unique, considering it is a non-nitrogenous opioid agonist and displays hallucinogenic effects similar to LSD 3, mescaline 4, and DMT 5 ( Fig. 1) while lacking structural similarity to these classical alkaloids.…”