'Carba'-carfentanil (trans isomer): a μ opioid receptor (MOR) partial agonist with a distinct binding mode.

ABSTRACT: There is strong evidence to indicate that a positively charged nitrogen of endogenous and exogenous opioid ligands forms a salt bridge with the Asp residue in the third transmembrane helix of opioid receptors. To further examine the role of this electrostatic interaction in opioid receptor binding and activation, we synthesized 'carba'-analogues of the highly potent μ opioid analgesic carfentanil (3), in which the piperidine nitrogen was replaced with a carbon. The resulting trans isomer (8b) showed reduced, but still significant MOR binding affinity (Ki(μ)=95.2nM) with no MOR versus DOR binding selectivity and was a MOR partial agonist. The cis isomer (8a) was essentially inactive. A MOR docking study indicated that 8b bound to the same binding pocket as parent 3, but its binding mode was

SUBMITTER: Weltrowska G 

PROVIDER: S-EPMC4149825 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature