In vivo pharmacology of SDZ 249-665, a novel, non-pungent capsaicin analogue

Capsaicin and analogues are valuable analgesic agents when administered to mammals, including humans. However, their pungency and the effects on the c ardiovascular and respiratory systems through their general activation of s mall calibre (nociceptive) primary afferents severely limit their use. Rece ntly, structure activity analysis revealed that the initial pungent and gen eral excitatory effects can be prevented by structural modifications in suc h a way that the analgesic activity is retained. Tn this paper we present S DZ 249-665, a capsaicin analogue which produced analgesia in the mouse and anti hyperalgesic effects in the rat and guinea pig. SDZ 249-665 was admini stered p.o., s.c. and i.v. in models of nociceptive pain, such as tail flic k latency in response to a noxious thermal stimulus and acetic acid-induced writhing in mice, and in models of inflammatory mechanical hyperalgesia in duced by turpentine or carrageenan in the rat and guinea pig, respectively. SDZ 249-665 was effective in the tail flick and the writhing assays and pr oduced significant anti-hyperalgesic effects in the inflammatory models. Th e efficacy of SDZ 245-665 was similar to that of capsaicin, however, it was significantly more potent. SDZ 249-655 did not produce any irritancy in a nose wipe assay in guinea pigs or an eye irritancy assay in rats, while cap saicin was clearly irritant in both cases. Furthermore, unlike capsaicin, S DZ 249-665 did not produce unwanted side effects such as bronchoconstrictio n and blood pressure changes in the analgesic/anti-hyperalgesic dose range. Thus, a clear analgesic therapeutic window exists for SDZ 249-665. In summ ary, SDZ 249-665 is a potent orally active, analgesic/anti-hyperalgesic age nt in mouse, rat and guinea pig. It lacks the excitatory effects associated with capsaicin and other close analogues, and therefore provides a clear t herapeutic window for use in painful conditions. In addition to this favour able profile, no sign of tolerance was detected after a 5 day repeated dose treatment. (C) 2000 International Association for the Study of Pain. publi shed by Elsevier Science B.V. All rights reserved.