Systematic Structure-Activity Relationship Study of Nalfurafine Analogues toward Development of Potentially Nonaddictive Pain Management Treatments.

Despite the availability of numerous pain medications, the current array of Food and Drug Administration-approved options falls short in adequately addressing pain states for numerous patients and consequently worsens the opioid crisis. Thus, it is imperative for basic research to develop novel and nonaddictive pain medications. Toward addressing this clinical goal, nalfurafine (NLF) was chosen as a lead and its structure-activity relationship (SAR) systematically studied through design, syntheses, and in vivo characterization of 24 analogues. Two analogues, 21 and 23, showed longer durations of action than NLF in a warm-water tail immersion assay, produced in vivo effects primarily mediated by KOR and DOR, penetrated the blood-brain barrier, and did not function as reinforcers. Additionally, 21 produced fewer sedative effects than NLF. Taken together, these results aid the understanding of NLF SAR and provide insights for future endeavors in developing novel nonaddictive therapeutics to treat pain.

Xylazine does not enhance fentanyl reinforcement in rats: A behavioral economic analysis.

The adulteration of illicit fentanyl with the alpha-2 agonist xylazine has been designated an emerging public health threat. The clinical rationale for combining fentanyl with xylazine is currently unclear, and the inability to study fentanyl/xylazine interactions in humans warrants the need for preclinical research. We studied fentanyl and xylazine pharmacodynamic and pharmacokinetic interactions in male and female rats using drug self-administration behavioral economic methods. Fentanyl, but not xylazine, functioned as a reinforcer under both fixed-ratio and progressive-ratio drug self-administration procedures. Xylazine combined with fentanyl at three fixed dose-proportion mixtures did not significantly alter fentanyl reinforcement as measured using behavioral economic analyses. Xylazine produced a proportion-dependent decrease in the behavioral economic Q0 endpoint compared to fentanyl alone. However, xylazine did not significantly alter fentanyl self-administration at FR1. Fentanyl and xylazine co-administration did not result in changes to pharmacokinetic endpoints. The present results demonstrate that xylazine does not enhance the addictive effects of fentanyl or alter fentanyl plasma concentrations. The premise for why illicitly manufacture fentanyl has been adulterated with xylazine remains to be determined.

Molecular Pharmacology Profiling of Phenylfentanil and Its Analogues to Understand the Putative Involvement of an Adrenergic Mechanism in Fentanyl-Induced Respiratory Depression.

While there are approved therapeutics to treat opioid overdoses, the need for treatments to reverse overdoses due to ultrapotent fentanyls remains unmet. This may be due in part to an adrenergic mechanism of fentanyls in addition to their stereotypical mu-opioid receptor (MOR) effects. Herein, we report our efforts to further understanding of the functions these distinct mechanisms impart. Employing the known MOR neutral antagonist phenylfentanil as a lead, 17 analogues were designed based on the concept of isosteric replacement. To probe mechanisms of action, these analogues were pharmacologically evaluated in vitro and in vivo, while in silico modeling studies were also conducted on phenylfentanil. While it did not indicate MOR involvement in vivo, phenylfentanil yielded respiratory minute volumes similar to those caused by fentanyl. Taken together with molecular modeling studies, these results indicated that respiratory effects of fentanyls may also correlate to inhibition of both α1A- and α1B-adrenergic receptors.

Sensitivity of a fentanyl-vs.-social interaction choice procedure to environmental and pharmacological manipulations.

Recent studies have shown that social interaction can serve as an alternative reinforcer to opioid self-administration under a choice context in rats. However, additional parametric studies are needed to evaluate the sensitivity of opioid-vs.-social interaction procedures relative to more established opioid-vs.-food procedures. The current study evaluated the sensitivity of a novel fentanyl-vs.-social interaction choice procedure to environmental and pharmacological manipulations previously shown to affect fentanyl-vs.-food choice. Male and female rats (responder rats; n = 6/sex) were trained to respond in a discrete-trial choice procedure for either 30-s access to a same-sex "partner" rat or an intravenous fentanyl infusion. Once trained, the effects of fentanyl unit dose (0, 0.32-10 µg/kg/inf), partner rat presence, opioid-dependence status, chronic naltrexone administration (0.032, 0.1 mg/kg/h), and response requirement for fentanyl self-administration (fixed ratio 1-320) were determined across weeks. The fentanyl-vs.-social interaction choice procedure was sensitive to the unit dose of fentanyl, chronic naltrexone treatment, and fentanyl response requirement. However, the magnitude of these effects on fentanyl choice was smaller than those reported in published fentanyl-vs.-food choice studies. Furthermore, fentanyl-vs.-social interaction choice was not sensitive to removal of the partner rat or opioid-dependence status. Minimal sex differences were detected. These results suggest that this fentanyl-vs.-social interaction choice procedure is less sensitive to environmental and pharmacological interventions than previously established opioid-vs.-food choice procedures. The observed discrepancy in sensitivity between the procedures suggests that social interaction may have qualitatively different reinforcing properties compared to more commonly assessed alternative reinforcers such as food (preclinical) or money (human laboratory).

Elucidating the binding mechanism of LPA species and analogs in an LPA4 receptor homology model.

Lysophosphatidic acid receptor 4 (LPA4) has emerged as a potential therapeutic target for the treatment of a variety of diseases, including cancer and obesity-induced diabetes, but its structure remains to be revealed. In the present work, a homology model of LPA4 was built for studying the binding mechanism of LPA species and analogs. Then five selected LPA species and analogs with structural variations in their phosphate groups, substitutions on the glycerol backbone, and fatty acyl chains were docked into the LPA4 model, followed by molecular dynamics simulations and energy analyses. The computational results revealed that the aliphatic residues located at the vertical cleft of LPA4 may form a hydrophobic environment for the fatty acyl moiety of LPA species and their analogs. Meanwhile, the positively charged residues in the central cavity of LPA4 may form ionic interactions with the negatively charged hydrophilic head group of LPA species and their analogs. In addition, it was noted that a different binding mode of the hydrophilic head group in each species with the central cavity of the LPA4 might lead to a special rearrangement of the fatty acyl moiety. Taken together, these results may facilitate understanding of the activation mechanism of LPA4 and help design selective ligands to modulate its function for therapeutic purposes.

Design of bivalent ligands targeting putative GPCR dimers.

G protein-coupled receptors (GPCRs) have been exploited as primary targets for drug discovery, and GPCR dimerization offers opportunities for drug design and disease treatment. An important strategy for targeting putative GPCR dimers is the use of bivalent ligands, which are single molecules that contain two pharmacophores connected through a spacer. Here, we discuss the selection of pharmacophores, the optimal length and chemical composition of the spacer, and the choice of spacer attachment points to the pharmacophores. Furthermore, we review the most recent advances (from 2018 to the present) in the design, discovery and development of bivalent ligands. We aim to reveal the state-of-the-art design strategy for bivalent ligands and provide insights into future opportunities in this promising field of drug discovery.

Stereoselective syntheses of 3-dehydroxynaltrexamines and N-methyl-3-dehydroxynaltrexamines.

Methodology is presented for the synthesis of 6α/ß-3-dehydroxynaltrexamines and 6α/ß- N-methyl-3-dehydroxynaltrexamines. A stereoselective route is provided for each target compound while a novel one-pot method for the synthesis of 6 α/ß-3-N-methyl-3-dehydroxynaltrexamines is also explored. These results enable the versatile and efficient preparation of key epoxymorphinan intermediates to facilitate future selective opioid ligand discovery and development.