Capsazepine

The first competitive TRPVl antagonist is capsazepine (3), a conforma-tionally constrained (9-demethyl thiourea analogue of capsaicin that emerged from a programme aimed at the optimization of the agonistic properties of capsaicinoids [66]. The second competitive antagonist to be... 

SB-366791 (18) emerged from screening an in-house library as a potent competitive inhibitor of both hTRPVl and rTRPVl, endowed with superior target selectivity compared to capsazepine [84]. Structure-activity relationships of SB-366791 remain to be reported. 

Enhanced TRPVl expression was demonstrated in IBD in man [17] and capsazepine was shown to attenuate disease severity in experimental colitis both in mice [145] and rats [146]. These findings confer a therapeutic potential for TRPVl antagonists in IBD and motility disorders [147, 148]. A related finding is the demonstration of increased TRPVl in the inflamed human oesophagus secondary to gastro-oesophageal reflux disorder [20]. 

Capsazepine attenuates interstitial oedema and neutrophil infiltration in the rat pancreas following infusion of the secretagogue cerulein [150]. 

Known antagonists of vanilloid receptors include capsazepine, which acts competitively but with low potency at the capsaicin binding sites (Bevan et al., 1992), iodo-RTX, which binds with high affinity (Wahl et al., 2001), the unselective antagonist ruthenium red (Amann and Maggi, 1991) and synthetic arginine-rich hexapeptides (Planells-Cases et al., 2000), which are putative channel blockers. 

Scheme 5 Chemical structures of known vanilloid receptor antagonists a, capsazepine, a weak but competitive synthetic compound from Novartis, b, iodo-resiniferatoxin, a potent and competitive synthetic compound from Novo Nordisk, c, ruthenium red, a weak, non-competitive and non-selective antagonists.

Najera, C. Lifhiated /Yarn i rioalkyl sulfones as mono and dinudeophiles in the preparation of nitrogen heterocydes application to the synthesis of capsazepine. Tetrahedron 1997,... 

Yue H-Y, Fujita T, Kawasaki Y, Kumamoto E (2004) AM404 enhances the spontaneous release of -glutamate in a manner sensitive to capsazepine in adult rat substantia gelatinosa neurones. Brain Res 1018 283... 

VANILLOID RECEPTOR ANTAGONISTS act at sites activated by sensory irritants, e.g. capsaicin see VANILLOID receptor agonists. Capsazepine, a synthetic compound developed out of vallinoids such as capsaicin, is a high-afflnity competitive vanilloid receptors antagonist. It is used as a pharmacological tool. There is some variation in affinity between different sites and species, suggesting receptor subtypes and species variants. Ruthenium Red also acts as an inhibitor at these sites in a non-competitive manner. 

Walpole. C.SJ. et al. (1994) The discovery of capsazepine. the first competitive antagonist of the sensory neuron excitants capsaicin and resiniferatoxin. /. Med. Chem..31.1942-1954. 

A cannabinoid receptor subtype has been found in the hippocampus that is responsive to WIN 55,212-2 and CP 55,940 and blocked by capsazepine (Hajos et al. 2001). These receptors are found on excitatory (pyramidal) axon terminals and have been shown to suppress glutamate release in CBi receptor knockout animals. 

Capsazepine (VRl) Huntington s disease Able to reverse antihyperkinetic effects of AM404 in 3NP-lesioned rats (Lastres-Becker et al. 2003a)... 

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