The Effects of Herkinorin, the First μ-Selective Ligand from a Salvinorin A-Derived Scaffold, in a Neuroendocrine Biomarker Assay in Nonhuman Primates

Abstract

Herkinorin is the first -opioid receptor-selective ligand from the salvinorin A diterpenoid scaffold. Herkinorin has relative Ͼ Ͼ ␦ binding selectivity, and it can act as an agonist at both -and -receptors, in vitro. These studies were the first in vivo evaluation of the effects of herkinorin in nonhuman primates, using prolactin release, a neuroendocrine biomarker assay that is responsive to both -and -agonists, as well as to compounds with limited ability to cross the blood-brain barrier. In cumulative dosing studies (0.01-0.32 mg/kg i.v.), herkinorin produced only small effects in gonadally intact males (n ϭ 4), but a more robust effect in females (n ϭ 4). Time course studies with herkinorin (0.32 mg/kg) confirmed this greater effectiveness in females and revealed a fast onset after i.v. administration (e.g., by 5-15 min). Antagonism experiments with different doses of nalmefene (0.01 and 0.1 mg/kg) caused dose-dependent and complete prevention of the effect of herkinorin in females. This is consistent with a principal -agonist effect of herkinorin, with likely partial contribution by -agonist effects. The peripherally selective antagonist quaternary naltrexone (1 mg/kg s.c.) caused approximately 70% reduction in the peak effect of herkinorin (0.32 mg/kg) in females, indicating that this effect of herkinorin is prominently mediated outside the blood-brain barrier.Salvinorin A, a plant-derived hallucinogenic diterpene, is a highly selective -opioid agonist, and a novel template for semisynthetic opioid analogs (Roth et al., 2002;Prisinzano and Rothman, 2008). One of these novel analogs is herkinorin, the first salvinorin-derived compound with -over -selectivity reported in the literature (Harding et al., 2005). Herkinorin has approximately 8-fold selectivity for -over -receptors and approximately 98-fold selectivity for -over ␦-receptors in competition binding assays (Harding et al., 2005). Herkinorin acts as a high-efficacy agonist at bothand -receptors in the guanosine 5Ј-O-(3-thio)triphosphate assay (Harding et al., 2005), with greater relative potency at -receptors. Herkinorin also displays some unique features in its interactions at the -receptor, such as decreased agonist-induced internalization (Groer et al., 2007;Xu et al., 2007).

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

“…This action proved useful in generating a cellular system with which to facilitate the identification of neutral MOP receptor antagonists (Sally et al, 2010). Studies in nonhuman primates provided neuroendocrine evidence for both MOP agonist and partial KOP agonist effects of herkinorin (Butelman et al, 2008). It is clear that more studies must be initiated to facilitate understanding of this unique ligand.…”

Antinociceptive effects of herkinorin, a MOP receptor agonist derived from salvinorin A in the formalin test in rats: New concepts in mu opioid receptor pharmacology: From a symposium on new concepts in mu-opioid pharmacology

“…The development of ligands that activate ERK in the absence of β-arrestin–MOP receptor interactions may provide valuable tools for studying this pharmacology further and could possibly lead to the discovery of novel compounds for the treatment chronic pain. Additional studies in non-human primates showed that herkinorin has opioid receptor mediated effects using prolactin release, a neuroendocrine biomarker assay that is responsive to both MOP and KOP agonists, as well as to compounds with limited ability to cross the blood-brain barrier (Butelman et al, 2008). More recently, we described three new derivatives of herkinorin with similar properties and one that promotes recruitment of β-arrestin-2 to the MOP receptor and receptor internalization (Tidgewell et al, 2008).…”

Herkinorin dilates cerebral vessels via kappa opioid receptor and cyclic adenosine monophosphate (cAMP) in a piglet model

“…Thus, herkinorin is the first non-opioid mu opioid receptor ligand (Butelman et al, 2008). Herkinorin was discovered in 2005 when various analogues of the natural product Salvinorin A were synthesized to study the structure and the function of neoclerodane diterpenes (Harding et al, 2005; Tidgewell et al, 2006).…”

“…Herkinorin is the first non-opioid mu agonist derived from the structurally related compound salvinorin A (Butelman et al, 2008). Since kappa opioid receptor activation elicits pial artery dilation (Armstead, 1998) and salvinorin A is a potent cerebral vasculature dilator that activates nitric oxide synthases, kappa receptors, and adenosine triphosphate-sensitive potassium channels (Su et al, 2011), it is likely that herkinorin could also elicit cerebrovasodilation.…”