Synthesis and in vitro pharmacological studies of C(4) modified salvinorin A analogues

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

doi:10.1016/j.bmcl.2005.06.092

Cited by 32 publications

(69 citation statements)

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“…Studies that aimed to identify metabolites of salvinorin A failed to find evidence of hydrolysis of the C-4 carbomethoxy moiety, suggesting that this group may be too sterically hindered for enzymatic modification. The stability of this group was also noted during attempts to modify salvinorin A using synthetic methods, because vigorous conditions are necessary to produce the C-18 acid (Tidgewell et al, 2004;Lee et al, 2005a;Munro et al, 2005a,b). Only one group (Kutrzeba et al, 2009b) reported screening specifically for epimerization of the C-8 position; however, no evidence of epimerization was found.…”

Section: A Metabolism Of Salvinorin Amentioning

confidence: 96%

“…The role of the 4-carbomethoxy group has also been explored (Lee et al, 2005aMunro et al, 2005b;Béguin et al, 2006). Reduction of this group was generally poorly tolerated (Fig.…”

Section: Structural Modifications Of the Trans-decalinmentioning

confidence: 99%

“…As with other analogs described previously, C-8 epimerization of 153-155 did not lead to increased affinity for KOP receptors. Hydrolysis of salvinorin A to the corresponding carboxylic acid (156) was not tolerated, resulting in a loss of affinity for KOP receptors (K i Ͼ 1000 nM); it is noteworthy that epimerization (8-epi-156) was reported to have largely restored affinity (K i ϭ 48.6 Ϯ 4.4 nM) and potency (K i ϭ 74.1 Ϯ 2.2 nM) (Lee et al, 2005a). Extension of the carbon chain of the methyl ester of salvinorin A to ethyl (157) and iso-propyl (158) resulted in a loss of affinity and potency at KOP receptors (Lee et al, 2005a).…”

Section: Structural Modifications Of the Trans-decalinmentioning

confidence: 99%

“…Hydrolysis of salvinorin A to the corresponding carboxylic acid (156) was not tolerated, resulting in a loss of affinity for KOP receptors (K i Ͼ 1000 nM); it is noteworthy that epimerization (8-epi-156) was reported to have largely restored affinity (K i ϭ 48.6 Ϯ 4.4 nM) and potency (K i ϭ 74.1 Ϯ 2.2 nM) (Lee et al, 2005a). Extension of the carbon chain of the methyl ester of salvinorin A to ethyl (157) and iso-propyl (158) resulted in a loss of affinity and potency at KOP receptors (Lee et al, 2005a). Further extension of the chain and incorporation of an acetylene function (159) did result in modest KOP receptor affinity (K i ϭ 201 nM); however, methoxymethyl (160) and methoxyethoxymethyl ester (161) modifications were poorly tolerated .…”

Section: Structural Modifications Of the Trans-decalinmentioning

confidence: 99%

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Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

2011

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Section: A Metabolism Of Salvinorin Amentioning

confidence: 96%

“…The role of the 4-carbomethoxy group has also been explored (Lee et al, 2005aMunro et al, 2005b;Béguin et al, 2006). Reduction of this group was generally poorly tolerated (Fig.…”

Section: Structural Modifications Of the Trans-decalinmentioning

confidence: 99%

Section: Structural Modifications Of the Trans-decalinmentioning

confidence: 99%

Section: Structural Modifications Of the Trans-decalinmentioning

confidence: 99%

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Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

2011

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“…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. [17] Growing concern in regards to its potential as a drug of abuse has led to prohibition of both plant material and active component in some countries (Australia, Denmark, Italy).…”

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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Opioid Receptor Ligands

McCurdy

Prisinzano

2010

Burger's Medicinal Chemistry and Drug Discovery

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Opioid agonists, exemplified by morphine, have been the most prescribed class of drugs for the management of moderate to severe pain for many years. These drugs have significant liabilities of addiction and constipation over long‐term use and acute overdoses can result in respiratory depression. For over thousands of years, opium and opium‐derived drugs have nonetheless been utilized for their therapeutic and recreational benefits. Due to their liabilities, medicinal chemists and clinicians have worked for years to discover novel agents or treatment courses that would be devoid of these side effects. Still to this day, there are no agents that meet these criteria. Therefore, efforts continue vigorously in the quest for drugs with potent analgesic effects without abuse or side‐effect potential. Many chemical classes have been sought after in this quest and the range from peptides to synthetic compounds to natural products. Morphine offered a template that was rigid and able to provide an enormous amount of structure–function relationships that many of the market analgesics are based on. To complicate matters, the endogenous opioid system is comprised of four distinct receptor subtypes. These receptors are all members of the G‐protein superfamily and are designated as mu (μ, MOP), delta (δ, DOP), kappa (κ, KOP), and nociception (ORL1, NOP). It has been realized over the years that a combination of activities at these receptors may result in agents that could be devoid of liabilities. Intensive efforts have been directed at improved probes for each receptor subtype and combinations of agonists and antagonists for combinations of these receptors. This review will discuss the structure–activity relationships, as they are currently understood, with regard to each of the major classes of compounds that interact with these protein targets.

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Synthesis and in vitro pharmacological studies of C(4) modified salvinorin A analogues

Cited by 32 publications

References 24 publications

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

Studies Towards the Synthesis of Salvinorin A

Opioid Receptor Ligands

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