Verifying the role of 3-hydroxy of 17-cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxy-6β-[(4'-pyridyl) carboxamido]morphinan derivatives via their binding affinity and selectivity profiles on opioid receptors

Abstract

In the present study, the role of 3-hydroxy group of a series of epoxymorphinan derivatives in their binding affinity and selectivity profiles toward the opioid receptors (ORs) has been investigated. It was found that the 3-hydroxy group was crucial for the binding affinity of these derivatives for all three ORs due to the fact that all the analogues 1a-e exhibited significantly higher binding affinities compared to their counterpart 3-dehydroxy ones 6a-e. Meanwhile most compounds carrying the 3-hydroxy group possessed similar selectivity profiles for the kappa opioid receptor over the mu opioid receptor as their corresponding 3-dehydroxy derivatives. [³⁵S]-GTPγS functional assay results indicated that the 3-hydroxy group of these epoxymorphinan derivatives was important for maintaining their potency on the ORs with various effects. Further molecular modeling studies helped comprehend the remarkably different binding affinity and functional profiles between compound 1c (NCP) and its 3-dehydroxy analogue 6c.

Keywords: 3-Hydroxy group; Binding affinity; Molecular docking; Opioid receptors; Selectivity.

Fig. 1.

Chemical structures of compounds 1a-e.

Fig. 2.

General structure of 4,5-epoxymorphinan containing the para-hydroxyphenylethylamine moiety.

Fig. 3.

Chemical structures of nalfurafine and compound CT-18

Fig. 4.

Chemical structures of levorphanol and compound ATPM

Fig. 5.

The chemical structures of NCP (a) and compound 6c (b). The structures with notions were derived from the optimized NCP_KOR^active and compound 6c_KOR^active complexes.

Fig. 6.

The binding modes of NCP_KOR^active, NCP_MOR^active, compound 6c_KOR^active, and compound 6c_MOR^inactive complexes after 100 ns MD simulations. The receptors were shown as cartoon models, the active KOR in light-pink, the active MOR in light-blue, and the inactive MOR in light-green. NCP, compound 6c, and key amino acid residues were shown as stick models. Carbon atoms: NCP in cyan; compound 6c in yellow; key amino acid residues of the KOR in magenta, and the MOR in orange. The dashed lines in yellow represented potential water-mediated hydrogen bonds. The key residues at the allosteric site of the MOR were shown as stick and ball models in magentas. The key residues at the allosteric site of the KOR were shown as stick and ball models in orange. The water molecules were shown as sphere models in red.

Fig. 6.

The binding modes of NCP_KOR^active, NCP_MOR^active, compound 6c_KOR^active, and compound 6c_MOR^inactive complexes after 100 ns MD simulations. The receptors were shown as cartoon models, the active KOR in light-pink, the active MOR in light-blue, and the inactive MOR in light-green. NCP, compound 6c, and key amino acid residues were shown as stick models. Carbon atoms: NCP in cyan; compound 6c in yellow; key amino acid residues of the KOR in magenta, and the MOR in orange. The dashed lines in yellow represented potential water-mediated hydrogen bonds. The key residues at the allosteric site of the MOR were shown as stick and ball models in magentas. The key residues at the allosteric site of the KOR were shown as stick and ball models in orange. The water molecules were shown as sphere models in red.

Scheme 1.

Synthesis of the target compounds 6a-e.