Novel TRPV1 Modulators with Reduced Pungency Induce Analgesic Effects in Mice

Abstract

Capsaicin, the compound in hot chili peppers responsible for their pungency and an agonist of the transient receptor potential cation channel, subfamily V, member 1 (TRPV1), has long been known to promote the desensitization of nociceptors at high concentrations. This has led to the utilization and implementation of topical capsaicin cream as an analgesic to treat acute and chronic pain. Critically, the application of capsaicin cream is limited due to capsaicin’s high pungency, which is experienced prior to analgesia. To combat this issue, novel capsaicin analogues were developed to provide analgesia with reduced pungency. Analogues reported in this paper add to and show some differences from previous structure–activity relationship (SAR) studies of capsaicin-like molecules against TRPV1, including the necessity of phenol in the aromatic “A-region”, the secondary amide in the “B-region”, and modifications in the hydrophobic “C-region”. This provided a new framework for de novo small-molecule design using capsaicin as the starting point. In this study, we describe the synthesis of capsaicin analogues, their in vitro activity in Ca2+ assays, and initial in vivo pungency and feasibility studies of capsaicin analogues YB-11 and YB-16 as analgesics. Our results demonstrate that male and female mice treated with YB capsaicin analogues showed diminished pain-associated behavior in the spontaneous formalin assay as well as reduced thermal sensitivity in the hotplate assay.

Solvent Effect on Base-Free Synthesis 4-Substituted 2-Oxazolines via Intramolecular Cyclodemesylation

“…2-Oxazolines also were obtained in moderate yields from hydroxylamides by replacing the hydroxyl group with a good leaving group, such as tosylate, mesylate, and halogen, and subsequent intramolecular cyclization using a base. [40][41][42][43][44] However, in these reactions, sometimes alongside 2-oxazolines, elimination products have been observed as byproducts. Clayden et al carried out the synthesis of 2-oxazolines in CH 2 Cl 2 without using a base or any reagent by intramolecular cyclization of a -mesylated amide.…”

Identification of a Partial and Selective TRPV1 Agonist CPIPC for Alleviation of Inflammatory Pain

“…However, potent TRPV1 agonist capsaicin causes an initial adverse effect of pungency and even an 8% capsaicin dermal patch can lead to erythema and pain at the site of application [ 33 ]. In contrast, a partial TRPV1 agonist MDR-652 and a subpotent capsaicin analogue YB-16 have been shown to be much weaker in causing pungency [ 21 , 34 ]. These observations suggest developing subpotent TRPV1 partial agonists might be an effective strategy to treat inflammatory and neuropathic pain with less toxicity.…”

Discovery of Potent and Selective Transient Receptor Potential Vanilloid 1 (TRPV1) Agonists with Analgesic Effects In Vivo Based on the Functional Conversion Induced by Altering the Orientation of the Indazole Core

“…Mice received administration (10 μL/paw) of capsaicin (0.2 μg/paw) or 28 (0.02, 0.2, and 2 μg/paw). Drugs were administered 30 min before the injection of formalin. , …”