Discovery and development of TRPV1 antagonists
[3] The discovery that the pungency of capsaicin is mediated through TRPV1 set the stage for further research of the function of the TRPV1 receptor, and preclinical studies showed evidence of its importance in numerous human diseases.
[1][4] These are the first agents acting by this mechanism that made their way into clinic for evaluation of their use as possible analgesics and therefore important targets for drug development.
Many discoveries are yet to be made, both in terms of the range of potential therapeutic applications in addition to analgesia for TRPV1 antagonists and it was only in the last decade where there has been a full understanding of the molecular mechanism.
[7] Capsaicin and RTX, elicit burning pain by activating a non-selective cation channel expressed on sensory nerve endings.
TRPV1 is also subject to regulation by changes in membrane potential and this intrinsic voltage-dependence is thought to underlie the gating mechanism of this non-selective cation channel which leads to the influx of sodium and calcium ions.
The functional activity of TRPV1 has been demonstrated, within the central nervous system, in the spinal cord and specific sites in the brain including the hypothalamus, cerebellum, locus coeruleus, periaqueductal grey and cortex.
Activation of TRPV1 sets off an influx of calcium and sodium ions which in turn initiates a cascade of events that result in membrane depolarization, neuronal firing and transduction of neural impulses.
Because these two amino acids are charged and located in the cytosolic part of TRPV1 receptor, the two regions are likely to be implicated in hydrophilic interaction of TRPV1 with vanilloids such as capsaicin and RTX.
[7] Initially, agonists were the major focus of the TRPV1 ligand development due to the analgesic effect resulting from desensitization of the receptor.
However, because of an initial burning effect of all natural vanilloid receptor agonists, including capsaicin, therapy becomes complicated and perhaps ineffective.
To avoid this persisting side effects of TRPV1 agonists, a focused consideration has been given to competitive antagonists as novel analgesic drugs.
Consistent with the critical role played by Tyr 667 in the interaction with key elements of the TRPV1 antagonist pharmacophore, site-directed mutagenesis studies have shown that exchanging this tyrosine for alanine in the rat TRPV1 receptor abolishes functional activity of TRPV1.
Because the intracellular ends of these helices extend past the membrane, they are likely to be flexible and may be part of the channel opening and closing process.
The phenolic hydroxide and amide moieties in capsaicin share potential multiple hydrogen bond interactions with the TRPV1 receptor.
The vanillyl and carbonyl linker contain polar groups capable of forming hydrogen bonds essential for activity, whereas the lipophilic moiety interacts with a corresponding cleft of the vanilloid binding site on TRPV1.
4a), the first competitive vanilloid antagonist,[14][9] reported by Novartis group, was aimed at assessing the effect of conformational constraint on the lipophilic C-region of capsaicin.
[16] Capsazepine competes for the capsaicin-binding site on TRPV1 however, due to low metabolic stability and poor pharmacokinetic properties the compound did not reach into clinical development.
[20] Several capsaicin analogs of the urea type were developed by acylation of homovanillylamine and related amines with different 4-(α-pyridyl)piperidine-1-acyl chlorides.
The presence of a polar amino moiety in the hydrophobic C region of capsacinoids was crucial to couple potency and hydrophilicity, mimicking similar observations that led to the discovery of phenylacetylrinvanil (fig.
5a and 5b) showed a higher selectivity profile against a wide variety of enzymes and channels[22] whereas the related very potent and specific TRPV1 antagonist A-425619 (fig.
6b) exhibited high antagonist potency showing good oral bio-availability in rats and a promising pharmacokinetic profile, boding well for clinical efficacy.
6c)that was shown in a postoperative pain trial to be able to decrease capsaicin-induced heat and mechanical hyperalgesia and to block central TRPV1 receptors.
7a) showed excellent potency at human, guinea pig, and rat TRPV1, a favorable in vitro drug metabolism and pharmacokinetics profile, and remarkable in vivo activity in an inflammatory pain model.
Starting from a 4,6-disubstituted benzimidazole lead structure, a series of 4,5-biarylimidazoles capable to block both capsaicin and acid-induced calcium influx in TRPV1-expressing Chinese hamster ovary cells.
8b), although it lacks any recognizable carbonyl motif it still potently blocks capsaicin, proton, and heat activation of TRPV1 in vitro and shows a good tolerability profile.
[37] Anesiva, another biotechnology company, has completed two Phase III trials of Adlea (ALGRX 4975), an injectable capsaicin.
