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 cardiovascular and respiratory systems through their general activation of small calibre (nociceptive) primary afferents severely limit their use. Recently, structure activity analysis revealed that the initial pungent and general excitatory effects can be prevented by structural modifications in such a way that the analgesic activity is retained. In this paper we present SDZ 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 administered p.o., s.c. and i.v. in models of nociceptive pain, such as tail flick latency in response to a noxious thermal stimulus and acetic acid-induced writhing in mice, and in models of inflammatory mechanical hyperalgesia induced 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 produced significant anti-hyperalgesic effects in the inflammatory models. The efficacy of SDZ 245-665 was similar to that of capsaicin, however, it was significantly more potent. SDZ 249-665 did not produce any irritancy in a nose wipe assay in guinea pigs or an eye irritancy assay in rats, while capsaicin was clearly irritant in both cases. Furthermore, unlike capsaicin, SDZ 249-665 did not produce unwanted side effects such as bronchoconstriction and blood pressure changes in the analgesic/anti-hyperalgesic dose range. Thus, a clear analgesic therapeutic window exists for SDZ 249-665. In summary, SDZ 249-665 is a potent orally active, analgesic/anti-hyperalgesic agent in mouse, rat and guinea pig. It lacks the excitatory effects associated with capsaicin and other close analogues, and therefore provides a clear therapeutic window for use in painful conditions. In addition to this favourable profile, no sign of tolerance was detected after a 5 day repeated dose treatment.
Urban
Laszlo
L
Novartis Institute for Medical Sciences, 5 Gower Place, London WC1E 6BN, UK.
Campbell
Elizabeth A
EA
Panesar
Moh
M
Patel
Sadhana
S
Chaudhry
Naureen
N
Kane
Steven
S
Buchheit
Karl-Heinz
KH
Sandells
Barrie
B
James
Iain F
IF
D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal; D001767:Blinking / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D016084:Bronchoconstriction / Q000187:drug effects; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D002351:Carrageenan; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005123:Eye; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D006168:Guinea Pigs; D006614:Hindlimb; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D007509:Irritants; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009619:Nociceptors / Q000187:drug effects; D009666:Nose; D009812:Odorants; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014425:Turpentine; D014508:Urea / Q000031:analogs & derivatives
D000700:Analgesics; D007509:Irritants; C425286:SDZ 249-665; D014508:Urea; D002351:Carrageenan; C071423:capsazepine; D002211:Capsaicin; D014425:Turpentine