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NEUROPHARMACOLOGY

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

The Rockefeller University, New York, New York (E.R.B., S.R., M.J.K.); Division of Medicinal and Natural Products Chemistry, University of Iowa, Iowa City, Iowa (D.S.S., T.E.P.); and Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas (D.S.S., A.W., T.E.P.)

Herkinorin is the first µ-opioid receptor-selective ligand from the salvinorin A diterpenoid scaffold. Herkinorin has relative µ > > binding selectivity, and it can act as an agonist at both µ- 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 µ- 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 = 4), but a more robust effect in females (n = 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 µ-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.

Address correspondence to: Dr. Eduardo Butelman, The Rockefeller University, Box 171, 1230 York Ave., New York, NY 10065. E-mail: butelme{at}rockefeller.edu