SA13353 (1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea) inhibits TNF-alpha production through the activation of capsaicin-sensitive afferent neurons mediated via transient receptor potential vanilloid 1 in vivo.
Tumor necrosis factor-alpha (TNF-alpha) is known to play a crucial role in the pathogenesis of rheumatoid arthritis. In the present study, we demonstrate the effects of SA13353 (1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea), a novel orally active inhibitor of TNF-alpha production, in animal models, and its mechanism of action on TNF-alpha production. SA13353 significantly inhibited lipopolysaccharide (LPS)-induced TNF-alpha production in a dose-dependent manner in rats. Moreover, SA13353 exhibited a binding affinity for the rat vanilloid receptor and increased neuropeptide release from the rat dorsal root ganglion neurons. However, its effects were blocked by pretreatment with the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine. The ability of SA13353 and capsaicin to inhibit LPS-induced TNF-alpha production was eliminated by sensory denervation or capsazepine pretreatment in vivo. Although they inhibited LPS-induced TNF-alpha production in mice, these effects were not observed in TRPV1 knockout mice. SA13353 provoked the release of neuropeptides without nerve inactivation, even when chronically administered to rats. These results suggest that SA13353 inhibits TNF-alpha production through activation of capsaicin-sensitive afferent neurons mediated via TRPV1 in vivo. Post-onset treatment of SA13353 strongly reduced the hindpaw swelling and joint destruction associated with collagen-induced arthritis in rats. Thus, SA13353 is expected to be a novel anti-arthritic agent with a unique mechanism of action.
Murai
Masaaki
M
Research and Development Center, Santen Pharmaceutical Co., Ltd., 8916-16 Takayama-cho, Ikoma-shi, Nara 630-0101, Japan. masaaki.murai@santen.co.jp <masaaki.murai@santen.co.jp>
Tsuji
Fumio
F
Nose
Masafumi
M
Seki
Iwao
I
Oki
Kenji
K
Setoguchi
Chikako
C
Suhara
Hiroshi
H
Sasano
Minoru
M
Aono
Hiroyuki
H
D000818:Animals; D001169:Arthritis, Experimental / Q000517:prevention & control; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013004:Somatostatin / Q000378:metabolism; D050916:TRPV Cation Channels / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
C530925:1-(2-(1-adamantyl)ethyl)-1-pentyl-3-(3-(4-pyridyl)propyl)urea; D008070:Lipopolysaccharides; D011725:Pyridines; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C493922:Trpv1 protein, rat; D014409:Tumor Necrosis Factor-alpha; D013004:Somatostatin; D014508:Urea; D015740:Calcitonin Gene-Related Peptide; C071423:capsazepine; D002211:Capsaicin