Premium
Discovery and pharmacological characterization of a novel potent inhibitor of diacylglycerol‐sensitive TRPC cation channels
Author(s) -
Maier T,
Follmann M,
Hessler G,
Kleemann HW,
Hachtel S,
Fuchs B,
Weissmann N,
Linz W,
Schmidt T,
Löhn M,
Schroeter K,
Wang L,
Rütten H,
Strübing C
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13151
Subject(s) - trpc , trpc6 , trpc5 , trpc3 , transient receptor potential channel , chemistry , pharmacology , hypoxic pulmonary vasoconstriction , patch clamp , diacylglycerol kinase , vasoconstriction , trpc1 , biophysics , medicine , receptor , biochemistry , biology , signal transduction , protein kinase c
Background and Purpose The cation channel transient receptor potential canonical ( TRPC ) 6 has been associated with several pathologies including focal segmental glomerulosclerosis, pulmonary hypertension and ischaemia reperfusion‐induced lung oedema. We set out to discover novel inhibitors of TRPC6 channels and investigate the therapeutic potential of these agents. Experimental Approach A library of potential TRPC channel inhibitors was designed and synthesized. Activity of the compounds was assessed by measuring intracellular Ca 2+ levels. The lead compound SAR 7334 was further characterized by whole‐cell patch‐clamp techniques. The effects of SAR 7334 on acute hypoxic pulmonary vasoconstriction ( HPV ) and systemic BP were investigated. Key Results SAR 7334 inhibited TRPC6 , TRPC 3 and TRPC 7‐mediated Ca 2+ influx into cells with IC 50 s of 9.5, 282 and 226 nM, whereas TRPC4 and TRPC 5‐mediated Ca 2+ entry was not affected. Patch‐clamp experiments confirmed that the compound blocked TRPC 6 currents with an IC 50 of 7.9 nM. Furthermore, SAR 7334 suppressed TRPC6 ‐dependent acute HPV in isolated perfused lungs from mice. Pharmacokinetic studies of SAR 7334 demonstrated that the compound was suitable for chronic oral administration. In an initial short‐term study, SAR 7334 did not change mean arterial pressure in spontaneously hypertensive rats ( SHR ). Conclusions and Implications Our results confirm the role of TRPC6 channels in hypoxic pulmonary vasoregulation and indicate that these channels are unlikely to play a major role in BP regulation in SHR . SAR 7334 is a novel, highly potent and bioavailable inhibitor of TRPC6 channels that opens new opportunities for the investigation of TRPC channel function in vivo .