Four sets of diastereomeric C9-alkenyl 5-phenylmorphans, varying in the length of the C9-alkenyl chain, were designed to examine the effect of these spatially distinct ligands on opioid receptors. Functional activity was obtained by forskolin-induced cAMP accumulation assays and several compounds were examined in the [35S]GTPgS assay and in an assay for respiratory depression. In each of the four sets, similarities and differences were observed dependent on the length of their C9-alkenyl chain and, most importantly, their stereochemistry. Three MOR antagonists were found to be as or more potent than naltrexone and, unlike naltrexone, none had MOR, KOR, or DOR agonist activity. Several potent MOR full agonists were obtained, and, of particular interest partial agonists were found that exhibited less respiratory depression than that caused by morphine. The effect of stereochemistry and the length of the C9-alkenyl chain was also explored using molecular modeling. The MOR antagonists were found to interact with the inactive (4DKL) MOR crystal structures and agonists were found to interact with the active (6DDF) MOR crystal structures. The comparison of their binding modes at the mouse MOR was used to gain insight into the structural basis for their stereochemically induced pharmacological differences.
|State||Published - Oct 2022|
Bibliographical noteFunding Information:
The work of D.R.C., A.S., A.E.J. and K.C.R. was supported by the NIH Intramural Research Program (IRP) of the National Institute on Drug Abuse and the National Institute of Alcohol Abuse and Alcoholism. The work of A.G., B.X. and L.S. was supported by the NIH Intramural Research Program (IRP) of the National Institute on Drug Abuse (Z1A DA000606—L.S.). The work of D.E.S. and N.N. was supported by P30-DA033934 and T32-DA007024, and the work of C.A.P. and J.B. was funded by DA047574. This work was also supported in part by DA051377 (to T.E.P.) and the Kentucky Medical Services Foundation Endowed Chair in Pharmacy (T.E.P.). The X-ray crystallographic work was supported by NIDA through an Interagency Agreement #Y1-DA1101 with the Naval Research Laboratory (NRL). NIH, DHHS.
© 2022 by the authors.
- KOR agonists and antagonists
- N-phenethyl-2-azabicyclo [3.3.1] nonan-5-yl) phenols
- active (6DDF) MOR crystal structures
- diastereomeric C9-alkenyl 5-phenylmorphans
- inactive (4DKL) MOR crystal structures
- molecular modeling and simulation
- respiratory depression
ASJC Scopus subject areas
- Analytical Chemistry
- Chemistry (miscellaneous)
- Molecular Medicine
- Pharmaceutical Science
- Drug Discovery
- Physical and Theoretical Chemistry
- Organic Chemistry