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Bioorg Med Chem. 2014 Sep 1;22(17):4581-6. doi: 10.1016/j.bmc.2014.07.033. Epub 2014 Jul 29.

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

Author information

1
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada.
2
Center for Drug Discovery, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
3
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada; Department of Pharmacology, Université de Montréal, Montreal, QC H3C 3J7, Canada. Electronic address: schillp@ircm.qc.ca.

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 somewhat different. A re-evaluation of the uncharged morphine derivative N-formylnormorphine (9) indicated that it was a weak MOR antagonist showing no preference for MOR over KOR. Taken together, the results indicate that deletion of the positively charged nitrogen in μ opioid analgesics reduces MOR binding affinity by 2-3 orders of magnitude and may have pronounced effects on the intrinsic efficacy and on the opioid receptor selectivity profile.

KEYWORDS:

Carfentanil; Opioid activity profiles; μ opioid receptor binding mode; ‘Carba’-carfentanil

PMID:
25129170
PMCID:
PMC4149825
DOI:
10.1016/j.bmc.2014.07.033
[Indexed for MEDLINE]
Free PMC Article

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