The hallucinogenic compound, salvinorin A, is a potent κ-opioid receptor (KOR) agonist. However, other target(s) than the KOR, such as the cannabinoid CB1 receptor, have been proposed to explain its multiple pharmacological actions. Here, we have evaluated the effect of salvinorin A in lipopolysaccharide (LPS)-stimulated macrophages as well as in models of inflammation in vivo. Salvinorin A (0.1-10 pM) reduced LPS-stimulated nitrite, TNF-α and IL-10 (but not IL-1β) levels as well as iNOS (but not COX-2) LPS-induced hyperexpression. The effect of salvinorin A on nitrite levels was reverted by the opioid antagonist naloxone, the KOR antagonist nor-binaltorphimine and by the CB1 antagonist rimonabant Salvinorin A also prevented KOR and CB1 hyperexpression induced by LPS. In vivo, salvinorin A reduced the LPS- and the carrageenan-induced paw oedema and formalin-induced inflammatory pain, in a nor-binaltorphimine and rimonabant-sensitive manner. It is concluded that salvinorin A-via KORs and CB1 receptors-exerts ultrapotent actions on macrophages and also shows moderate antinflammatory effects in vivo.
Our results suggest that the drugs based on the structure of SA have the potential to become valuable antiinflammatory or analgesic therapeutics for the treatment of GI diseases.
The synthesis and in vitro evaluation of a new series of salvinorin A analogues substituted at the C(2) position with natural amino acids is reported. Compound 12, containing Val, displayed high affinity and full agonist activity at the kappa-opioid receptor. Analogues with bulky and/or aromatic residues were inactive, showing the importance of size and electronegativity of C(2)-substituents for binding affinity of salvinorin A derivatives.
KeywordsSalvia divinorum; salvinorin B; neoclerodane diterpenoid; natural amino acids; opioid receptor ligands A neoclerodane diterpenoid salvinorin A (SA) (1), the active ingredient of the Mexican plant Salvia divinorum, is a selective kappa-opioid receptor (KOR) agonist with potent in vivo activity (Fig. 1). 1 Recent reports point out a potential role in the treatment of functional gastrointestinal (GI) disorders, which is in accord with the traditional use of S. divinorum extracts. SA potently inhibits smooth muscle contractility and motility in vivo in the upper and lower GI, as well as influences the epithelial ion transport in a KOR-dependent manner under both physiological and pathophysiological conditions. 2 Pharmacokinetic studies in animals and in humans indicate that SA is rapidly degraded and that its in vivo effects are short-lasting, regardless of route of administration. 3 Therefore numerous attempts have been made to synthesize SA derivatives with potent affinity at KOR and prolonged in vivo actions. 2 The structure-activity relationship (SAR) studies of SA have demonstrated that the size and electronegativity of the substituent at the C(2) position is critical for activity at opioid receptors. It was shown that SA derivatives with spatially restrained (3-4 carbon atoms) lipophilic groups at C(2) display highest binding affinity and potency at KOR.4 -9 However, incorporation of non-lipophilic substituents, such as amines and amino acids also
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