Application of Bivalent Bioisostere Concept on Design and Discovery of Potent Opioid Receptor Modulators

Abstract

Here, we described the structural modification of previously identified μ opioid receptor (MOR) antagonist NAN, a 6α-N-7′-indolyl substituted naltrexamine derivative, and its 6β-N-2′-indolyl substituted analogue INTA by adopting the concept of “bivalent bioisostere”. Three newly prepared opioid ligands, 25 (NBF), 31, and 38, were identified as potent MOR antagonists both in vitro and in vivo. Moreover, these three compounds significantly antagonized DAMGO-induced intracellular calcium flux and displayed varying degrees of inhibition on cAMP production. Furthermore, NBF produced much less significant withdrawal effects than naloxone in morphine-pelleted mice. Molecular modeling studies revealed that these bivalent bioisosteres may adopt similar binding modes in the MOR and the “address” portions of them may have negative or positive allosteric modulation effects on the function of their “message” portions compared with NAN and INTA. Collectively, our successful application of the “bivalent bioisostere concept” identified a promising lead to develop novel therapeutic agents toward opioid use disorder treatments.

Structure-Based Design and Development of Chemical Probes Targeting Putative MOR-CCR5 Heterodimers to Inhibit Opioid Exacerbated HIV-1 Infectivity

“…The [ 35 S]­GTPγS functional assay was carried out in mMOR-CHO cells to define the relative efficacy of these bivalent ligands to activate the MOR, as previously illustrated. , E max values of all ligands were measured relative to that of the maximal stimulated response produced by the full MOR agonist DAMGO. VZMC013 produced minimal stimulation of the MOR and displayed insignificant apparent efficacy (% E max = 9.22%), similar to those of the previously designed bivalent ligand VZMC001 and the parent compound naltrexone (Table ).…”

“…The pharmacological profiles of the three newly prepared MOR bivalent ligands were further characterized for their effects on MOR-dependent intracellular Ca 2+ signaling in an mMOR-CHO cell line that was transfected with chimeric Gqi5 protein as previously described . No agonism was observed for VZMC013 at varying concentrations (Figure S2a), compared with the known MOR agonist DAMGO (EC 50 = 36.3 ± 1.85 nM).…”

“…13 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(3′,13′dioxo-1′-phenyl-2′,15′-dioxa-4′,12′-diazaheptadecanamido)morphinan (28a). The title compound was prepared following the general amide coupling procedure by reacting acid 27a with 6βnaltrexamine hydrochloride (prepared according to the method reported by our group) 61 in DMF overnight. The crude product was further purified by column chromatography to furnish 28a as a white solid.…”

Design, Synthesis, and Biological Evaluation of NAP Isosteres: A Switch from Peripheral to Central Nervous System Acting Mu-Opioid Receptor Antagonists

“…Our laboratories have been engaged in identifying novel chemical entities toward developing selective opioid receptor ligands by employing the “message-address concept” . Our drug design efforts have led to the development of a small molecule library encompassing different substituents on the epoxymorphinan skeleton. − Previously, we reported a highly selective MOR antagonist 17-cyclopropylmethyl-3,14-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl)­carboxamido]­morphinan (NAP), which showed high binding affinity for the MOR and at least 500-fold and 150-fold selectivity over the DOR and KOR in vitro, respectively. , However, further in vivo pharmacological characterization of NAP revealed that it showed limited potency with an AD 50 of 4.51 (95% CL, 2.45–8.20) mg/kg, in part because of its constrained ability to penetrate the blood–brain barrier (BBB), making NAP a peripherally acting selective MOR antagonist. , Collectively, this data encouraged us to explore NAP as a lead for centrally acting MOR-selective antagonists with potential to treat OUD. Herein, we report our efforts toward developing centrally acting MOR antagonists by applying an isosteric replacement as a lead optimization strategy.…”

Computational Methods for Understanding the Selectivity and Signal Transduction Mechanism of Aminomethyl Tetrahydronaphthalene to Opioid Receptors

“…Additionally, opioid antagonists such as naloxone and naltrexone were used to treat opioid abuse, which did not have the side effects related to the MOR agonism. Some scientists make many efforts to develop newly selective MOR antagonists or μ/κ opioid receptor dual ligands for the treatment of opioid use disorder ( Figure 2 ) [ 17 , 18 , 19 ], and NFP could produce significantly fewer withdrawal symptoms than naloxone at similar doses in vivo.…”