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 Chemjournal_title
Bioorganic & medicinal chemistryauthors
Weltrowska G,Lemieux C,Chung NN,Guo JJ,Wilkes BC,Schiller PWdoi
10.1016/j.bmc.2014.07.033subject
Has Abstractpub_date
2014-09-01 00:00:00pages
4581-6issue
17eissn
0968-0896issn
1464-3391pii
S0968-0896(14)00549-5journal_volume
22pub_type
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