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.
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