Synthesis of novel triplet drugs with 1,3,5-trioxazatriquinane skeletons and their pharmacologies. 3: synthesis of novel triplet drugs with the bis(epoxymethano) or bis(dimethylepoxymethano) structure (double-capped triplet)

Bioorg Med Chem Lett. 2012 Dec 15;22(24):7551-4. doi: 10.1016/j.bmcl.2012.10.023. Epub 2012 Oct 13.

Abstract

Novel double-capped triplet drugs, which have one pharmacophore unit and two epoxymethano or dimethylepoxymethano structures (termed cap or diMe-cap structures, respectively) were synthesized. Key intermediate oxazoline 16 derived from acetone enabled the effective synthesis of double-capped triplets. SYK-134 (7a) and SYK-135 (8a) with N-cyclopropylmethyl substituent and cap structures showed selectivities for the κ opioid receptor. On the other hand, the N-Me series exhibited selectivities for the μ opioid receptor. The double-capped triplet drugs with diMe-cap structures preferred the μ receptor independently of their N-substituents. SYK-385 (19b), one of the μ-selective double-capped triplet drugs, showed the highest selectivity for the μ receptor among the reported μ-selective nonpeptide ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Guinea Pigs
  • Heterocyclic Compounds, 4 or More Rings / chemical synthesis
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Methane / analogs & derivatives
  • Methane / chemistry*
  • Mice
  • Molecular Structure
  • Receptors, Opioid, kappa / metabolism*
  • Receptors, Opioid, mu / metabolism*
  • Structure-Activity Relationship

Substances

  • 1,3,5-trioxazatriquinane
  • Heterocyclic Compounds, 4 or More Rings
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Methane