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

Abstract

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

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

“…In contrast, salvinorin A (10 mg/ kg) elicited neither antinociception nor hypothermia 30 min after administration to rats. The findings reported by Wang et al (2008) suggest that salvinorin B MOM is a potent and efficacious KOP receptor agonist with longer lasting in vivo effects than salvinorin A. The current findings that salvinorin B MOM and salvinorin B EOM produce substitution in rats trained to discriminate U69,593 support previous reports that these agents are KOP agonists and that they are more potent than salvinorin A.…”

“…However, these analogs show reduced binding affinity and retain the rapidly metabolized acetate which may be responsible for salvinorin A's brief duration of action. The pharmacological properties of salvinorin B MOM were recently characterized by Wang et al (2008). This compound was reported to bind to KOP receptors with high selectivity and it displayed an approximately threefold higher affinity compared to U50,488 and salvinorin A. Salvinorin B MOM also acted as a full agonist at kappa receptors in functional assays, being approximately fivefold to sevenfold more potent than U50,488 and salvinorin A.…”

“…There is also considerable evidence that alterations in KOP systems may underlie some of the neuroadaptive changes associated with compulsive drug seeking and relapse and the search for KOPs as possible pharmacotherapeutic agents has led to the recent development of synthetic analogs of salvinorin A with greater potency and a longer duration of action Wang et al 2008). Preclinical in vivo screening of these novel compounds is a crucial step in developing potential therapeutic agents for the treatment of substance abuse and dependence.…”

Kappa opioids and the modulation of pain

“…However, the antinociceptive effects of salvinorin A are short-lived (McCurdy et al 2006). More recently, MOMSal B, a semi-synthetic derivative of salvinorin A, was found to produce antinociception using the hot plate test in a dose-dependent manner in rats and has longer lasting in vivo effects than salvinorin A (Wang et al 2008). Additional work suggests that protecting salvinorin A derivatives from metabolism will prolong duration of action, but only when administered by routes giving slow absorption (Hooker et al 2009).…”

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

“…However, a subsequent study by McCurdy et al (2006) reported that salvinorin A administered intraperitoneally to mice produced transient and relatively weak antinociception as well as hypothermia. In a subsequent study, Wang et al (2008) reported that the presumably metabolically stabilized salvinorin A analog 2-methoxymethyl-salvinorin B (94) produced antinociception and hypothermia in rats. The discrepant results reported by Wang et al (2005) and McCurdy et al (2006) are most likely explained by differences in route of administration and pharmacokinetics.…”