Pharmacological activities of optically pure enantiomers of the κ opioid agonist, U50,488, and its cis diastereomer: evidence for three κ receptor subtypes

Richard B. Rothman, Charles P France, Victor Bykov, Brian R. De Costa, Arthur E. Jacobson, James H. Woods, Kenner C. Rice

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

De Costa et al. (FEBS Lett. 223, 335; 1987) recently described the synthesis of optically pure enantiomers of (±)-trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U50,488). In the present study we examined the in vitro opioid receptor selectivity of (-)-(1S,2S)-U50,488, (+)-(1R,2R)-U50,488 and (±)-cis-3,4-di-chloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (the cis diasteromers of U50,488), as well as their pharmacological activities in rhesus monkeys. Using [3H]5α,7α,8β-(-)-N-methyl-N-[7-1-pyrrolidinyl)-1-oxaspiro (4,5)dec-8-yl]-phenyl-benzeneacetamide([3H]U69,593) to label κ binding sites of guinea pig membranes, the apparent dissociation constants of the enantiomers hadU50,488 were 0.89 and 299 nM, for the (S,S) and (R,R) enantiomers, respectively. The (-)-cis and (+)-cis diastereomers had apparent Kds of 167 and 2715 nM, respectively. Binding surface analysis of the interaction of (-)-(1S,2S)-U50,488 with κ binding sites labeled by [3H]bremazocine resolved two binding sites at which (-)-(1S,2S)-U50,488 had Kds of 30 and 10485 nM, respectively. The (±)-cis, (-)-cis and (+)-cis diastereomers of U50,488 (1 μM) did not inhibit [3H]bremazocine binding. Rhesus monkeys were trained to discriminate ethylketocyclazocine (EKC) and saline. All compounds tested substituted completely for EKC. The order of potency was (-)-(1S,2S)-U50,488 > (±)-U50,488 > (±)-cisdiastereomer of U50,488 > (+)-(1R,2R)-U50,488. In tests of analgesia, (-)-(1S,2S)-U50,488 was 2-4 times more potent than (±)-U50,488, while (±)-cis diastereomer of U50,488 and (+)-(1R,2R)-U50,488 were inactive at the highest doses tested (32 mg/kg). Taken collectively, these data indicate that the pharmacologically active enantiomer of U50,488 is (-)-(1S,2S)-U50,488, and provide preliminary evidence for three subtypes of κ binding sites in guinea pig brain.

Original languageEnglish (US)
Pages (from-to)345-353
Number of pages9
JournalEuropean Journal of Pharmacology
Volume167
Issue number3
DOIs
StatePublished - Aug 29 1989
Externally publishedYes

Fingerprint

Opioid Analgesics
Ethylketocyclazocine
Binding Sites
Pharmacology
Macaca mulatta
Benzeneacetamides
Guinea Pigs
(trans)-Isomer 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide
Opioid Receptors
Pain Measurement
Membranes
Brain
bremazocine

Keywords

  • 488
  • cis diastereomer of U-50
  • Enantiomers
  • Opiate receptors
  • U-50,488
  • U-69,593
  • κ Opioid receptors

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Pharmacological activities of optically pure enantiomers of the κ opioid agonist, U50,488, and its cis diastereomer : evidence for three κ receptor subtypes. / Rothman, Richard B.; France, Charles P; Bykov, Victor; De Costa, Brian R.; Jacobson, Arthur E.; Woods, James H.; Rice, Kenner C.

In: European Journal of Pharmacology, Vol. 167, No. 3, 29.08.1989, p. 345-353.

Research output: Contribution to journalArticle

Rothman, Richard B. ; France, Charles P ; Bykov, Victor ; De Costa, Brian R. ; Jacobson, Arthur E. ; Woods, James H. ; Rice, Kenner C. / Pharmacological activities of optically pure enantiomers of the κ opioid agonist, U50,488, and its cis diastereomer : evidence for three κ receptor subtypes. In: European Journal of Pharmacology. 1989 ; Vol. 167, No. 3. pp. 345-353.
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AU - Bykov, Victor

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N2 - De Costa et al. (FEBS Lett. 223, 335; 1987) recently described the synthesis of optically pure enantiomers of (±)-trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U50,488). In the present study we examined the in vitro opioid receptor selectivity of (-)-(1S,2S)-U50,488, (+)-(1R,2R)-U50,488 and (±)-cis-3,4-di-chloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (the cis diasteromers of U50,488), as well as their pharmacological activities in rhesus monkeys. Using [3H]5α,7α,8β-(-)-N-methyl-N-[7-1-pyrrolidinyl)-1-oxaspiro (4,5)dec-8-yl]-phenyl-benzeneacetamide([3H]U69,593) to label κ binding sites of guinea pig membranes, the apparent dissociation constants of the enantiomers hadU50,488 were 0.89 and 299 nM, for the (S,S) and (R,R) enantiomers, respectively. The (-)-cis and (+)-cis diastereomers had apparent Kds of 167 and 2715 nM, respectively. Binding surface analysis of the interaction of (-)-(1S,2S)-U50,488 with κ binding sites labeled by [3H]bremazocine resolved two binding sites at which (-)-(1S,2S)-U50,488 had Kds of 30 and 10485 nM, respectively. The (±)-cis, (-)-cis and (+)-cis diastereomers of U50,488 (1 μM) did not inhibit [3H]bremazocine binding. Rhesus monkeys were trained to discriminate ethylketocyclazocine (EKC) and saline. All compounds tested substituted completely for EKC. The order of potency was (-)-(1S,2S)-U50,488 > (±)-U50,488 > (±)-cisdiastereomer of U50,488 > (+)-(1R,2R)-U50,488. In tests of analgesia, (-)-(1S,2S)-U50,488 was 2-4 times more potent than (±)-U50,488, while (±)-cis diastereomer of U50,488 and (+)-(1R,2R)-U50,488 were inactive at the highest doses tested (32 mg/kg). Taken collectively, these data indicate that the pharmacologically active enantiomer of U50,488 is (-)-(1S,2S)-U50,488, and provide preliminary evidence for three subtypes of κ binding sites in guinea pig brain.

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