Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

Cunningham, Christopher W.; Rothman, Richard B.; Prisinzano, Thomas E.

doi:10.1124/pr.110.003244

Cited by 106 publications

(145 citation statements)

References 215 publications

(319 reference statements)

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“…The 1 H NMR data of acrylate 4a displayed typical acrylate protons as a doublet of doublets at δ 6.20 (J = 8.0, 16.4 Hz), and two doublets at δ 6.49 (J = 16.4 Hz), and 5.93 (J = 8.0 Hz). The corresponding data of 4b [21] 3 ). The second product (4d) proved to be the non-conjugated isomer of 4c.…”

Section: Chemistrymentioning

confidence: 99%

“…Considering the fact that Michael acceptors may also react reversibly with nucleophiles [15][16][17][18][19], such compounds may provide potential drug candidates for CNS disorders. Herein, we report the synthesis of a new series of potential Michael acceptor-type salvinorin A derivatives modified at C-2, a position that has been found to be crucial for a high-affinity binding to the KOR [3]. Among the compounds synthesized and tested were a set of cinnamic acid derivatives, which were selected with the knowledge that salvinorin derivatives bearing an aromatic substituent at the C-2 position (the most noteworthy of which is 2-O-benzoylsalvinorin B or herkinorin [20]) exhibit a marked change in the compounds' pharmacological profile compared to salvinorin A; in particular, these compounds tended to exhibit reduced affinity for KOR and increased affinity for MOR [3].…”

Section: Introductionmentioning

confidence: 99%

“…Herein, we report the synthesis of a new series of potential Michael acceptor-type salvinorin A derivatives modified at C-2, a position that has been found to be crucial for a high-affinity binding to the KOR [3]. Among the compounds synthesized and tested were a set of cinnamic acid derivatives, which were selected with the knowledge that salvinorin derivatives bearing an aromatic substituent at the C-2 position (the most noteworthy of which is 2-O-benzoylsalvinorin B or herkinorin [20]) exhibit a marked change in the compounds' pharmacological profile compared to salvinorin A; in particular, these compounds tended to exhibit reduced affinity for KOR and increased affinity for MOR [3]. At the same time we hypothesized that adding a conjugated bond to the aromatic system might further increase MOR affinity as the introduction of alkene moieties at the C-2 position showed a similar shift in pharmacological profile [21].…”

Section: Introductionmentioning

confidence: 99%

“…It gained significant scientific interest as the only non-nitrogenous KOR agonist with no apparent structural similarity to other ligands. This has encouraged several research groups to study the structure-activity relationships of 1, and a plethora of salvinorin A derivatives has been synthesized over the past decade [3][4][5][6][7][8]. Some of these analogues exhibit interesting pharmacological profiles from full KOR agonist to partial DOR or MOR agonist and antagonists.…”

Section: Introductionmentioning

confidence: 99%

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Michael Acceptor Approach to the Design of New Salvinorin A- Based High Affinity Ligands to the Kappa-Opioid Receptor

Polepally¹,

Setola²,

Vardy³

et al. 2012

Planta Med

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The neoclerodane diterpenoid salvinorin A is a major secondary metabolite isolated from the psychoactive plant Salvia divinorum. Salvinorin A has been shown to have high affinity and selectivity for the κ-opioid receptor (KOR). To study the ligand-receptor interactions that occur between salvinorin A and the KOR, a new series of salvinorin A derivatives bearing potentially reactive Michael acceptor functional groups at C-2 was synthesized and used to probe the salvinorin A binding site. The κ-, δ-, and μ-opioid receptor (KOR, DOR and MOR, respectively) binding affinities and KOR efficacies were measured for the new compounds. Although none showed wash-resistant irreversible binding, most of them showed high affinity for the KOR, and some exhibited dual affinity to KOR and MOR. Molecular modeling techniques based on the recently-determined crystal structure of the KOR combined with results from mutagenesis studies, competitive binding, functional assays and structure-activity relationships, and previous salvinorin A-KOR interaction models were used to identify putative interaction modes of the new compounds with the KOR and MOR. Supporting informationScatter plot of pK i vs. pIC 50 at KOR for salvinorin A and tested analogs, 1 H, 13 C NMR spectra and chromatographic (HPLC) data for synthesized compounds 4a-4h and 5a-5n are presented in the Supporting Information.

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Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Michael Acceptor Approach to the Design of New Salvinorin A- Based High Affinity Ligands to the Kappa-Opioid Receptor

Polepally¹,

Setola²,

Vardy³

et al. 2012

Planta Med

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“…Salvia divinorum Epling & Játiva es una planta que hace parte de la cultura de los indígenas Mazatecos de Oaxaca en México [1][2][3][4] y es conocida común-mente como hierba de los dioses, ska pastora, ska maría pastora, hierba maría o menta mágica, entre otros [5][6][7][8].…”

Section: Característicasunclassified

Salvinorina A: terpeno alucinógeno presente en Salvia divinorum Epling & Játiva

2017

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Resumen. Tema y alcance: el objetivo de esta revisión es presentar los estudios químicos que se han realizado sobre Salvia divinorum E&J en estos últimos años. Características: desde la década de 1990 hasta hoy se ha incrementado la distribución y el uso de Salvia divinorum E&J para "fines recreativos", debido a sus efectos alucinógenos y a su fácil acceso. Sus efectos en el organismo se han relacionado con las de otras sustancias como: delta-9-thc en la marihuana, dmt, lsd, mdma, pcp y ketamina. Hallazgos: las investigaciones químicas realizadas en otros países sobre Salvia divinorum E&J se enfocan en los procesos de extracción, determinación, cuantificación, análisis y biosíntesis de Salvinorina A, compuesto químico al cual se le atribuye la bioactividad de la planta. Este compuesto es considerado como uno de los alucinógenos más potentes de origen natural, además de ser química y estructuralmente único, puesto que fue el primer diterpeno conocido con actividad psicoactiva. Conclusiones: la presente revisión encontró que en los últimos años las investigaciones químicas en Salvia divinorum E&J están enfocadas a través del uso de cromatografía de gases y cromatografía líquida en diversas matrices como hojas, sangre, orina y agua, con el fin de determinar la Salvinorina A y otros metabolitos presentes en la planta. En una de las investigaciones, comprobaron por rmn y hr-esi-ms que la biosíntesis de Salvinorina A está dada por la ruta metabó-lica del ácido mevalónico y la ruta del metileritritol fosfato, las cuales corresponden a las rutas metabólicas para la biosíntesis de terpenos.

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Salvia divinorum Epling & Jativa and Salvinorin A

Barceloux

2012

Medical Toxicology of Drug Abuse

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Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

Cited by 106 publications

References 215 publications

Michael Acceptor Approach to the Design of New Salvinorin A- Based High Affinity Ligands to the Kappa-Opioid Receptor

Michael Acceptor Approach to the Design of New Salvinorin A- Based High Affinity Ligands to the Kappa-Opioid Receptor

Salvinorina A: terpeno alucinógeno presente en Salvia divinorum Epling & Játiva

Salvia divinorum Epling & Jativa and Salvinorin A

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