Salvinorin A Analogs as Probes in Opioid Pharmacology

Abstract

Recently, the biosynthetic route of 2a was studied using the incorporation of [1-13 C]glucose, [CH 3-13 C]methionine, and [1-13 C;3,4-2 H 2 ]-1-deoxy-D-xylulose into its structure. 58 Neoclerodane 2a, like other terpenoids, results from the assembly of isopentenylpyrophosphate and dimethylallyl pyrophosphate to form geranylgeranyl pyrophosphate (31) (Figure 4). 59 Cyclization of 31 affords the labdanyl cation (32), which after several methyl shifts yields clerodane pyrophosphate (33). Further oxidation, acetylation, and methylation of 33 constructs 2a. Despite low incorporation, feeding experiments with [1-13 C;3,4-2 H 2 ]-1-deoxy-D-xylulose (DOX) yielded a pattern of incorporation consistent with the deoxyxylulose phosphate pathway. 58 Furthermore, enrichment of the C-23 methoxy group suggests the participation of an S-adenosyl-L-methionine dependent type III O-methyltransferase. However, the enzymes responsible for the oxygenation of 33 remain uncharacterized. 3. Structure-Activity Relationships of Salvinorin A Analogs Over the last 150 years, opioid receptor ligands have remained an active area in central nervous system (CNS) drug discovery. Opioid agonists are used clinically for the management of cancer pain, chronic pain, and cough and to treat diaherra. 28 Opioid antagonists, such as naloxone and naltrexone, are used to treat opioid overdose, narcotic addiction, and alcohol dependence. 60 Preclinical studies suggest that opioid agonists may have utility in treating stimulant

Comparison of the discriminative stimulus effects of salvinorin A and its derivatives to U69,593 and U50,488 in rats

“…Until recently, the most specific of these compounds were U69,593, U50,488 and their congeners spiradoline and enadoline, which have limited efficacy following oral administration Endoh et al 1999). In a recent report, Prisinzano and Rothman (2008) suggested that analogs of the chemicals isolated from S. divinorum may prove to be excellent research tools and give greater insight into opioid receptor-mediated phenomena. Some synthetic analogs of salvinorin A with altered pharmacology have recently been reported (partial agonists and antagonists).…”

Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity

“…1), was identified as a potent and highly selective κOR agonist (18). The structural novelty of Sal A led to extensive structure-activity relationship (SAR) studies through hemisynthetic approaches (19). The furyl-δ-lactone group of Sal A ( Fig.…”

Molecular Aspects of Opioid Receptors and Opioid Receptor Painkillers

“…Numerous structure-activity relations (SAR) studies have been carried out on opioid receptor ligands to determine features that drive affinity or efficacy with the goal of generating more effective therapeutic compounds, (Eguchi 2004;Metcalf and Coop 2005;Prisinzano and Rothman 2008;Yongye, Appel et al 2009, amongst others). SAR studies employing site-directed substitutions and constraints of endogenous peptides, as well as modifications of morphine have provided valuable insights about the pharmacophoric features, ligand selectivity and biological roles of opioid receptors.…”