Further modification of salvinorin A (1a), the major active component of Salvia divinorum, has resulted in the synthesis of novel neoclerodane diterpenes with opioid receptor affinity and activity. We report in this study that oxadiazole 11a and salvidivin A (12a), a photooxygenation product of 1a, have been identified as the first neoclerodane diterpenes with kappa antagonist activity. This indicates that additional structural modifications of 1a may lead to analogues with higher potency and utility as drug abuse medications.

Flavonoids have been recognized as the active ingredients of many medicinal plant extracts due to interactions with proteins via phenolic groups and low toxicity. Here, we report the investigation of the flavonoid core as a potential new scaffold for the development of opioid receptor ligands. Biological results suggest that stereochemistry of the C2 and C3 positions is important for antagonist activity and selectivity. Our results also suggest that the actions of Hypericum perforatum may be mediated in part by opioid receptors.At present, effective pharmacotherapies have yet to be developed for cocaine and methamphetamine dependence. A large body of evidence in animal models indicates that κ receptors (and their endogenous opioid peptide ligands, e.g., the dynorphins) modulate the effects of these CNS stimulants. 1,2 The κ receptor/dynorphin system is thought to be part of the brain's counter-regulatory response to enhanced dopaminergic activity, which is thought to be a major initial event underlying drug-induced reinforcement and abuse potential. In particular, κ antagonists attenuate the reinstatement of extinguished drug-taking behavior (a model of relapse). 3Among the first nonpeptide κ antagonists identified were those derived from the nonselective antagonist naltrexone (1) such as nor-BNI (nor-binaltorphimine, 2a) and GNTI (5′-guanidinonaltrindole, 2b) (Chart 1). 4,5 While 2a has been extensively used to study κ opioid receptors, its pharmacological properties are not optimal, and it exhibits a much longer than expected half-life in vivo. 6 Further study 7-11 of its structure-activity relationships identified 2b as a κ antagonist. 12,13 Compound 2b has increased potency in vivo compared to 2a, but unfortunately also has a slow onset of action and a long half-life in vivo. 14 Recently, Thomas et al. identified several novel κ opioid receptor antagonists from several classes of opioids. 15-18 κ-Selective antagonists were identified from the 4-phenylpiperidine and the 5-phenylmorphan classes of opioids. In particular, JDTic ((3R)-7-hydroxy-N-(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-pi-peridinyl]methyl-2-methylpropyl-1,2,3,4-tetrahydro-3-isoquinolin-ecarboxamide, 3) was shown to be a more potent κ antagonist than 2a. 16 Biological studies have shown that 3 blocks κ-agonist-induced antinociception in mice and squirrel monkey and antagonizes κ-agonist-induced diuresis in rats. 19 A more recent study illustrated that 3 is effective in decreasing withdrawal signs in rodents, indicating 3 may find some application in the treatment of opiate abuse. 20 Furthemore, 3 significantly reduced footshock-induced reinstatement of cocaine responding in rats and decreased immobility and increased swimming time in the forced swim stress test similar to the antidepressant * To whom correspondence should be addressed. Tel: (319) Additional screening showed that 4 had significant δ opioid receptor affinity (K i = 36 nM) in vitro. 36 However, it was not known whether 4 was an agonist or an antagonist at δ opio...