Structure–Activity Relationship Studies of 6α- and 6β-Indolylacetamidonaltrexamine Derivatives as Bitopic Mu Opioid Receptor Modulators and Elaboration of the “Message-Address Concept” To Comprehend Their Functional Conversion

Abstract

Structure-activity relationship (SAR) studies of numerous opioid ligands have shown that introduction of a methyl or ethyl group on the tertiary amino group at position 17 of the epoxymorphinan skeleton generally results in a mu opioid receptor (MOR) agonist while introduction of a cyclopropylmethyl group typically leads to an antagonist. Furthermore, it has been shown that introduction of heterocyclic ring systems at position 6 can favor antagonism. However, it was reported that 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(2'-indolyl)acetamido]morphinan (INTA), which bears a cyclopropylmethyl group at position 17 and an indole ring at position 6, acted as a MOR agonist. We herein report a SAR study on INTA with a series of its complementary derivatives to understand how introduction of an indole moiety with α or β linkage at position 6 of the epoxymorphinan skeleton may influence ligand function. Interestingly, one of INTA derivatives, compound 15 (NAN) was identified as a MOR antagonist both in vitro and in vivo. Molecular modeling studies revealed that INTA and NAN may interact with different domains of the MOR allosteric binding site. In addition, INTA may interact with W293 and N150 residues found in the orthosteric site to stabilize MOR activation conformation while NAN does not. These results suggest that INTA and NAN may be bitopic ligands and the type of allosteric interactions with the MOR influence their functional activity. These insights along with our enriched comprehension of the "message-address" concept will to benefit future ligand design.

N-Phenethyl Substitution in 14-Methoxy-N-methylmorphinan-6-ones Turns Selective µ Opioid Receptor Ligands into Dual µ/δ Opioid Receptor Agonists

“…mitragynine pseudoindoxyl) and peptides (i.e. DAMGO) has been described 37,38,[41][42][43][44] . The interaction with Y148 is also recognized as an important requirement for ligands (small molecules and peptides) to bind to the µOR 37,38,[41][42][43][44] .…”

“…DAMGO) has been described 37,38,[41][42][43][44] . The interaction with Y148 is also recognized as an important requirement for ligands (small molecules and peptides) to bind to the µOR 37,38,[41][42][43][44] . In this study, the oxygen of the partially saturated furan ring (E-ring) of the morphinan system serves as a hydrogen bond acceptor for Y148 in both series of N-methyl (1)(2)(3)(4) and N-phenethyl substituted morphinans (1a-4a).…”

“…Several studies have evidenced MD simulations as an effective approach to examine binding modes between opioid receptors and their ligands 39,[41][42][43][44] . In order to further validate the binding modes of morphinans 1-4 and 1a-4a depicted using molecular docking, we performed all-atoms MD simulations of the µOR as described 47 .…”

Identification and characterization of plant-derived alkaloids, corydine and corydaline, as novel mu opioid receptor agonists

“…Using these settings, we retrieved 15 virtual hits. The central role of Asp147 and Tyr148 of peptides, morphinans ligands, and other chemotypes for binding to the MOR is well recognized 22,[24][25][26][27][28][29][30][31][32][33][34] . Further, both of these interactions appeared to be critical for ligand binding in our previous study 26 .…”

“…In the search for ligands with new chemotypes and further understanding the mechanism by which known ligands (i.e. small molecules and peptides) bind and activate the MOR, structure-based discovery campaigns have used the high-resolution MOR structures to computationally investigate diverse molecules [25][26][27][28][29][30][31] . We have previously reported on a virtual screening campaign that led to the identification of novel chemotypes that displayed MOR antagonism in vitro and in vivo 26 .…”