Abstract
Salvinorin (Sal) A is a naturally occurring, selective κ 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 ∼3-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 5′-O-(3-[35S]thio)triphosphate binding and was ∼5- and ∼7-fold more potent than U50,488H and Sal A, respectively. In Chinese hamster ovary cells stably expressing KOPR, all three κ 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 ∼3 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.
Footnotes
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This study was supported by National Institutes of Health Grants R01-DA019688 and R01-DA019688 (to D.Y.W.L.), R01-DA022694 (to S.M.R.), and R01-DA17302 to (L.-Y.L.-C.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.132142.
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ABBREVIATIONS: KOPR, κ opioid receptor; (–)U50,488H, (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate; U69,593, (+)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide; ICI 204,448, (RS)-[3-[1-[[(3,4-dichlorophenyl) acetyl]methylamino]-2-(1-pyrrolidinyl)ethyl]phenoxy]acetic acid; asimadoline, N-[(1S)-2-[(3S)-3-hydroxypyrrolidin-1-yl]-1-phenylethyl]-N-methyl-2,2-di(phenyl)acetamide; nalfurafine, 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl) acrylamido]morphinan hydrochloride; Sal, salvinorin; norBNI, norbinaltorphimine; MOM, 2-methoxymethyl; [35S]GTPγS, guanosine 5′-O-(3-[35S]thio)triphosphate; CHO, Chinese hamster ovary; CHO-FLAG-hKOPR, CHO cells with stable expression of FLAG-tagged human κ opioid receptor; ANOVA, analysis of variance; %MPA, percentage of maximum possible analgesia; enadoline, 2-(1-benzofuran-4-yl)-N-methyl-N-[(5R,7S,8S)-7-pyrrolidin-1-yl-1-oxaspiro[4.5]decan-8-yl]acetamide; ΔTb, change in body temperature.
- Received September 30, 2007.
- Accepted December 17, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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