Synthesis and in vitro pharmacological studies of new C(2) modified salvinorin A analogues

Lee, David Y.W.; Karnati, Vishnu Vardhan Reddy; He, Minsheng; Liu‐Chen, Lee‐Yuan; Kondaveti, Leelakrishna; Ma, Zhongjun; Wang, Yulin; Chen, Yong; Béguin, Cécile; Carlezon, William A.; Cohen, Bruce M.

doi:10.1016/j.bmcl.2005.05.048

Cited by 63 publications

(107 citation statements)

References 23 publications

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“…Efforts have been devoted to characterize its structure-activity relationship and to develop more metabolically stable agonists and antagonists for use as pharmacological tools and perhaps as therapeutic agents. We have synthesized a series of C(2) derivatives of Sal A (Béguin et al, 2005;Lee et al, 2005a), one of which, 2-methoxymethyl (MOM)-Sal B (Fig. 1), is a selective KOPR full agonist more potent than Sal A or U50,488H (Lee et al, 2005a).…”

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confidence: 99%

2-Methoxymethyl-Salvinorin B Is a Potent κ Opioid Receptor Agonist with Longer Lasting Action in Vivo Than Salvinorin A

Wang¹,

Chen²,

Xu³

et al. 2007

J Pharmacol Exp Ther

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Salvinorin (Sal) A is a naturally occurring, selective opioid receptor (KOPR) agonist with a short duration of action in vivo. Pharmacological properties of a C(2) derivative, 2-methoxymethyl (MOM)-Sal B, were characterized. MOM-Sal B bound to KOPR with high selectivity and displayed ϳ3-fold higher affinity than U50,488H [(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate] and Sal A. It acted as a full agonist at KOPR in guanosine 5Ј-O-(3-[ 35 S]thio)triphosphate binding and was ϳ5-and ϳ7-fold more potent than U50,488H and Sal A, respectively. In Chinese hamster ovary cells stably expressing KOPR, all three agonists internalized or down-regulated KOPR to similar extents, with MOM-Sal B being the most potent. In mice, MOM-Sal B (0.05-1 mg/kg s.c.) caused immediate and dose-dependent immobility lasting ϳ3 h, which was blocked by norbinaltorphimine. In contrast, ambulation in a Y-maze was increased when rats received MOM-Sal B (1-5 mg/kg s.c.). In addition, MOM-Sal B (0.5-5 mg/kg i.p.) produced antinociception (hot-plate test) and hypothermia in a dose-dependent manner in rats. MOM-Sal B was more potent than U50,488H in both tests and more efficacious than U50,488H in the hot-plate test. These latter two in vivo effects were blocked by norbinaltorphimine, indicating KOPR-mediated actions. Sal A at 10 mg/kg elicited neither antinociception nor hypothermia 30 min after administration to rats. In summary, MOM-Sal B is a potent and efficacious KOPR agonist with longer lasting in vivo effects than Sal A.Activation of the opioid receptor (KOPR), one of three major types of opioid receptors, produces many effects including analgesia, dysphoria, antipruritis, water diuresis, and hypothermia (Liu-Chen, 2004). Many selective nonpeptide KOPR agonists have been synthesized; most are arylacetamide compounds, including U50,488H, U69,593, ICI 204,448, and asimadoline. Nalfurafine is an exception, being an epoxymorphinan.Chewing or smoking the leaves of Salvia divinorum or drinking juice of crushed leaves causes hallucinations in humans (Siebert, 1994). Salvinorin (Sal) A (Fig. 1), a neoclerodane diterpene, was isolated and identified as the main active ingredient (Valdés, 1994). In a large scale screening of G protein-coupled receptors, transporters, and ion channels by radioligand binding assays, Roth et al. (2002) found that Sal A was a highly potent and selective agonist for the KOPR. Since then, several pharmacological studies on Sal A have been performed. Sal A binds to KOPR with a high affinity similar to U50,488H, a prototypic selective KOPR agonist. It does not show significant affinities to and ␦ opioid receptors or the nociceptin/orphanin FQ receptor . Sal A is reported to be more selective for KOPR than U50,488H or U69,593 (Beguin et al., 2008). Sal A acts as a very potent full agonist at KOPR in [35 S]GTP␥S binding, intracellular calcium mobilization, and potassium conductance assays (Chavkin et al., 2004;Wang et al., 2005). Sal A

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2-Methoxymethyl-Salvinorin B Is a Potent κ Opioid Receptor Agonist with Longer Lasting Action in Vivo Than Salvinorin A

Wang¹,

Chen²,

Xu³

et al. 2007

J Pharmacol Exp Ther

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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

“…Estructura química de la Salvinorina A [17] La Salvinorina A es un compuesto químico que fue aislado por Ortega et al en 1982 y de allí se clasificó como un diterpeno, al cual se le atribuye la bioactividad de Salvia divinorum E&J [1-4, 17, 38]. Este compuesto es considerado como uno de los alucinógenos más potentes de origen natural, además de ser química y estructuralmente único, dado que fue el primer diterpeno neocloredano (compuesto químico con cuatro estereocentros contiguos) conocido con actividad psicoactiva, pues carece de nitrógeno básico [1,3,7,11,17,20,21,[39][40][41].…”

Section: Metabolitos Secundarios: Terpenosunclassified

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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“…Recent efforts to elucidate structure-activity relationships of 1 have involved the modification of the C2-acetoxy and C4-ester substituents. The semisynthetic methoxymethyl C2 analogue has shown increased potency as a KOR agonist, [14] and affinity for the µ-opioid receptor has been reported in analogues containing aromatic C2-ester substituents. [15] C4-modified analogues have been reported to possess reduced binding affinity [16] and by-products from ester hydrolysis under basic conditions have been shown to involve the oxidation of ring A.…”

Section: Introductionmentioning

confidence: 99%

Studies Towards the Synthesis of Salvinorin A

2006

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Salvinorin A 1, a psychoactive neoclerodane diterpenoid from the Mexican sage S. divinorum, has gained interest as a selective κ-opioid receptor agonist. Non-racemic 3-furylamines 9a and 9b have been prepared from (+)-pseudoephedrine and (−)-ephedrine for application in the stereoselective synthesis of the ketone ring of 1. Diels-Alder reaction of 9b with methyl acrylate in aqueous media, followed by selective ether bridge cleavage, has allowed access to the cyclohexenone 17 with preservation of stereochemistry at C2. A model route to the lactone ring has also been achieved through a one-pot deconjugation/esterification procedure of 2-bromocrotonyl chloride 20 to the furyl alcohol 19 followed by Reformatski-mediated ring closure.

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Synthesis and in vitro pharmacological studies of new C(2) modified salvinorin A analogues

Cited by 63 publications

References 23 publications

2-Methoxymethyl-Salvinorin B Is a Potent κ Opioid Receptor Agonist with Longer Lasting Action in Vivo Than Salvinorin A

2-Methoxymethyl-Salvinorin B Is a Potent κ Opioid Receptor Agonist with Longer Lasting Action in Vivo Than Salvinorin A

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

Studies Towards the Synthesis of Salvinorin A

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