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In‐vitro and in‐vivo pharmacology of a novel TRPV1 receptor antagonist: JNJ38748021
Author(s) -
Bhattacharya Anindya,
Hawryluk Natalie A,
Merit Jeffrey E,
Nasser Nadia,
Ao Hong,
Wang Qi,
Tham ChuiSe,
Maher Michael P,
Kansagara Mena,
Scott Brian P,
Hack Michael D,
Breitenbucher James G,
Chaplan Sandra R,
Wickenden Alan D
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.720.12
Subject(s) - trpv1 , chemistry , capsaicin , pharmacology , resiniferatoxin , antagonist , hyperalgesia , capsazepine , in vivo , receptor antagonist , receptor , transient receptor potential channel , medicine , nociception , biochemistry , biology , microbiology and biotechnology
TRPV1 is a polymodal nociceptor that plays a critical role in modulating sensory thresholds and is an attractive target for analgesia and inflammatory disorders. Here we report a novel tetrahydropyrimidoazepine, JNJ38748021 that attenuated capsaicin activation of the recombinant TRPV1 receptor with a pIC 50 of 7.2 ± 0.05 against both the rat and the human isoforms (FLIPR). Likewise, JNJ38748021 was also an equipotent antagonist against both pH and anandamide‐induced activation of rat and human TRPV1. The compound also displaced resiniferatoxin in a binding assay with a pK i of 7.2 (rat) and 7.7 (human). Against the native form of TRPV1, JNJ38748021 blocked capsaicin‐induced rat bladder contractility with a pK B of 7.1 (isometric contraction of isolated tissue) and a pIC 50 of 6.8 in isolated rat DRG cultured neurons (whole‐cell patch clamp). JNJ38748021 was modestly orally bioavailable (35%) in rats at 10 mg/kg with a C max of about 1 μM. The clearance and half‐life of the compound was 2.2 l/hr/kg and 1.43 hr, respectively in rats. In a pharmacodynamic model of capsaicin‐induced hypotension, the plasma concentration for half effect (Cp 50 ) was 1 μM. JNJ38748021 (10 and 30 mg/kg, p.o) was efficacious in reversing carrageen‐induced thermal hyperalgesia in rats. In conclusion, JNJ38748021 is a novel TRPV1 antagonist with analgesic properties.