Abstract
Several preclinical studies indicate that selective κ-opioid receptor (KOR) antagonists have antidepressant-like effects, whereas KOR agonists have opposite effects, suggesting that each might be useful in the treatment of mood abnormalities. Salvinorin A (salvA) is a valuable KOR agonist for further study due to its high potency and receptor selectivity. However, it has short lasting effects in vivo and limited oral bioavailability, probably due to acetate metabolism. We compared the in vitro receptor binding selectivity of salvA and four analogs containing an ethyl ether (EE), isopropylamine (IPA), N-methylacetamide (NMA), or N-methylpropionamide (NMP) at C-2. All compounds showed high binding affinity for the KOR (Ki = 0.11–6.3 nM), although only salvA, EE, and NMA exhibited KOR selectivity. In a liver microsomal assay, salvA was least stable, whereas NMA and IPA displayed slower metabolic transformations. Intraperitoneal (i.p.) administration of salvA, NMA, and NMP dose-dependently elevated brain reward thresholds in the intracranial self-administration (ICSS) test, consistent with prodepressive-like KOR agonist effects. NMA and NMP were equipotent to salvA but displayed longer lasting effects (6- and 10-fold, respectively). A dose of salvA with prominent effects in the ICSS test after i.p. administration (2.0 mg/kg) was inactive after oral administration, whereas the same oral dose of NMA elevated ICSS thresholds. These studies suggest that, although salvA and NMA are similar in potency and selectivity as KOR agonists in vitro, NMA has improved stability and longer lasting actions that might make it more useful for studies of KOR agonist effects in animals and humans.
Footnotes
-
This work was supported by National Alliance for Research on Schizophrenia and Depression (to C.B.), the National Institute of Mental Health Grant MH063266 (to W.C.), the Shervert Frazier Research Institute (B.M.C.), the Stanley Medical Research Institute (to C.B. and B.M.C.), and the National Institute of Drug Abuse Grant DA13429 (to L.L.C.). Ki values were generously provided by the NIMH-PDSP contract number NOIMH32004 (to B.L.R.) and by National Institute of Drug Abuse Grant RO1DA016264 (to B.L.R.).
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.107.129023.
-
ABBREVIATIONS: KOR, κ-opioid receptor; MOR, μ-opioid receptor; DOR, δ-opioid receptor; 3FLB, diethyl-2,4-di-[3-fluorophenyl]-3,7-dimethyl3,7-diazabicyclo[3.3.1]nonane-9-one-1,5-dicarboxylate; 5HT, serotonin; DMSO, dimethyl sulfoxide; NIMH-PDSP, National Institute of Mental Health Psychoactive Drug Screening Program; EE, salvinorin B ethyl ether; ICSS, intracranial self-stimulation; IPA, N-(2-propyl)-2-amido salvinorin B (using IUPAC functional replacement nomenclature); MPA, mobile phase A; MPB, mobile phase B; NMA, N-acetyl-N-methyl-2-amido salvinorin B (using IUPAC functional replacement nomenclature); NMP, N-propionyl-N-methyl-2-amido salvinorin B (using IUPAC functional replacement nomenclature); salvA, salvinorin A; SAR, structure-activity relationship; TRK-820, 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[Nmethyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride; U50,488, (1S,2S)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride; U69,593, (+)-(5R,7S,8S)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzenacetamide; h, human; r, rat; D, dopamine; H, histamine; M, muscarinic; CI-977, [5R-(5α,7α,8β)]-N-methyl-N-[7-(1-pyrrolidinyl)1-oxaspiro[4,5]dec-8-yl]-4-benzofuranacetamide; ICI-199441, 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide; PD-117302, (±)-trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzothiophene-4-acetamide.
-
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received July 23, 2007.
- Accepted October 18, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|