Highly Selective Kappa Opioid Analgesics. 4. Synthesis of Some Conformationally Restricted Naphthalene Derivatives With High Receptor Affinity and Selectivity

J Med Chem. 1991 Jan;34(1):190-4. doi: 10.1021/jm00105a028.

Abstract

This paper describes the synthesis and kappa and mu opioid receptor binding affinity of some conformationally restrained derivatives of the arylacetamide group in the selective kappa opioid receptor agonist (+/-)-trans-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzo [b]thiophene-4-acetamide monohydrochloride (1,PD117302), which is an analogue of U-50, 488. The methyl-substituted derivatives (+/-)-trans-N, alpha-dimethyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzo-[b] thiophene-4-acetamide monohydrochloride (6a,b) possess significantly weaker affinity than 1 for the kappa opioid receptor (Ki = 172 and 3.7 nM, respectively). It is proposed that this is due to the conformational restriction imposed by the methyl group of 6. In order to test this proposal the acenaphthene derivative and the 4,5-dihydro-3H-naphtho [1,8-bc]thiophene derivative were prepared. The acenaphthene derivative (+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro [4.5]dec-8-yl]acenaphthenecarboxamide monohydrochloride (9) was found to have high kappa opioid receptor affinity and selectivity (kappa Ki = 0.37 +/- 0.05 nM, mu/kappa = 659, delta/kappa = 1562) and is 100 times more potent than morphine as an analgesic in the rat paw pressure test for analgesia after intravenous administration (MPE50 = 0.014 and 1.4 mg/kg, respectively). The 4,5-dihydro-3H-naphtho[1,8-bc]thiophene derivative (-)-4,5-dihydro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro [4.5]dec-8-yl]-3H-naphthol[1,8-bc]thiophene-5-carboxamide p-toluenesulfonate (17) also has high kappa opioid receptor affinity and selectivity (kappa Ki = 4.65 nM, mu/kappa = 109).

MeSH terms

  • Analgesics / chemical synthesis*
  • Animals
  • Indicators and Reagents
  • Molecular Conformation
  • Molecular Structure
  • Naphthalenes / chemical synthesis*
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology
  • Receptors, Opioid / drug effects*
  • Receptors, Opioid / metabolism
  • Receptors, Opioid, kappa
  • Structure-Activity Relationship

Substances

  • Analgesics
  • Indicators and Reagents
  • Naphthalenes
  • Receptors, Opioid
  • Receptors, Opioid, kappa