'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 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.

journal_name

Bioorg Med Chem

authors

Weltrowska G,Lemieux C,Chung NN,Guo JJ,Wilkes BC,Schiller PW

doi

10.1016/j.bmc.2014.07.033

subject

Has Abstract

pub_date

2014-09-01 00:00:00

pages

4581-6

issue

17

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(14)00549-5

journal_volume

22

pub_type

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