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Preclinical characterization of three transient receptor potential vanilloid receptor 1 antagonists for early use in human intradermal microdose analgesic studies
Author(s) -
Sjögren E.,
Halldin M.M.,
Stålberg O.,
SundgrenAndersson A.K.
Publication year - 2018
Publication title -
european journal of pain
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.305
H-Index - 109
eISSN - 1532-2149
pISSN - 1090-3801
DOI - 10.1002/ejp.1175
Subject(s) - trpv1 , pharmacology , transient receptor potential channel , capsaicin , dorsal root ganglion , in vivo , chinese hamster ovary cell , analgesic , receptor , chemistry , medicine , biology , biochemistry , anatomy , dorsum , microbiology and biotechnology
Background The transient receptor potential vanilloid receptor 1 ( TRPV 1) is a nonselective cation channel involved in the mediation of peripheral pain to the central nervous system. As such, the TRPV 1 is an accessible molecular target that lends itself well to the understanding of nociceptive signalling. This study encompasses preclinical investigations of three molecules with the prospect to establish them as suitable analgesic model compounds in human intradermal pain relief studies. Methods The inhibitory effectiveness was evaluated by means of in vitro assays, TRPV 1 expressing Chinese hamster ovary cells ( CHO ‐K1) and rat dorsal root ganglion cultures in fluorescent imaging plate reader and whole cell patch clamp systems, as well as in vivo by capsaicin‐evoked pain‐related behavioural response studies in rat. Secondary pharmacology, pharmacokinetics and preclinical safety were also assessed. Results In vitro , all three compounds were effective at inhibiting capsaicin‐activated TRPV 1. The concentration producing 50% inhibition ( IC 50 ) determined was in the range of 3–32 nmol/L and 10–501 nmol/L using CHO ‐K1 and dorsal root ganglion cultures, respectively. In vivo , all compounds showed dose‐dependent reduction in capsaicin‐evoked pain‐related behavioural responses in rat. None of the three compounds displayed any significant activity on any of the secondary targets tested. The compounds were also shown to be safe from a toxicological, drug metabolism and pharmacokinetic perspective, for usage in microgram doses in the human skin. Conclusion The investigated model compounds displayed ideal compound characteristics as pharmacological and translational tools to address efficacy on the human native TRPV 1 target in human skin in situ . Significance This work details the pharmaceutical work‐up of three TRPV 1‐active investigational compounds, to obtain regulatory approval, for subsequent use in humans. This fast and cost‐effective preclinical development path may impact research beyond the pain management area, as it allows human target engagement information gathering early in drug development.