PHARMACOLOGICAL PROFILES OF A NOVEL TACHY KININ NK-2 RECEPTOR ANTAGONIST, TAC-363

We examined the pharmacological profiles of a novel tachykinin NK-2 re ceptor antagonist, )-L-glutaminyl-L-tryptophyl-alpha-azaphenylalanine 2-benzyloxyethylamide (TAG-363). In vitro studies showed that TAG-363 caused a rightward shift of the contraction response curve with a slig ht inhibition of maximal response for the neurokinin A (NKA)-induced c ontraction of the hamster trachea and parallel rightward shift of the curve for the substance P (SP)-induced contraction of the guinea-pig i leum. The pA(2) values were 9.82 and 8.42 on the contraction by NKA an d SP, respectively. The selectivity of TAC-363 to NK-2 receptor was 25 times higher than that to NK-1 receptor. The compound did not affect the histamine and acetylcholine-induced contraction of the guinea-pig ileum. Intravenous administration (0.1-1 mg/kg) of the compound inhibi ted dose-dependently both NKA- and capsaicin-induced bronchoconstricti on in guinea-pigs. The inhibitory effect of the compound lasted up to 60 min on NKA-induced bronchoconstriction in guinea-pigs. These result s suggest that TAC-363 is a potent and selective NK-2 receptor antagon ist, which is effective in vitro and in vivo. It may be useful in the treatment of NKA-dependent pathology, especially bronchial asthma.