ligand gated ion channel that has been implicated in mediation of many types of pain and therefore studied most extensively. The first competitive antagonist, capsazepine, was first described in 1990; since then, several TRPV1 antagonists have entered clinical trials as analgesic agents. Should these new chemical entities relieve symptoms of chronic pain, then this class of compounds may offer one of the first novel mechanisms for the treatment of pain in many years.[clarification needed][1][2]
History
Figure 1. Chili pepper
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. In the years to come it will be clearer if TRPV1 antagonists can fulfill their potential.[1][5][6]
.
In addition to these sites in N- and C-termini of TRPV1, a region in the intracellular linker sited in the transmembrane domain, called 'the TM3 region', has been shown to be critical for hydrophobic interaction with vanilloids. The TM3 region is considered to be necessary for binding to vanilloids. It is surrounded by the hydrophobic environment because of its placement in the
plasma membrane. Now it is recognized as an important link in hydrophobic interaction with capsaicin. The binding sites Arg 114 and Glu 761 and the TM3 region in TRPV1, together consist of a binding pocket to vanilloids.[9][2]
Drug design
Agonists
Figure 2. Chemical structure of capsaicin
Capsaicin (fig. 2), a naturally occurring vanilloid, is the best known TRPV1 agonist. Resiniferatoxin (RTX) is another naturally occurring vanilloid that exhibits TRPV1 agonistic activity. It is more potent than capsaicin and is currently in development as a sensory neuron desensitizing agent.[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. Attempts to make synthetic agonists with good separation between excitatory effects and the analgesic effects have not been successful. To avoid this persisting side effects of TRPV1 agonists, a focused consideration has been given to competitive antagonists as novel analgesic drugs.[8]
Antagonists
Intense efforts have been carried out to design both
competitive and non-competitive TRPV1 antagonists. Antagonists that bind to the agonist binding site, and lock the channel in the closed, nonconductive state are competitive antagonists. In contrast, antagonists that interact with additional binding sites on the receptor structure preventing receptor opening by the agonist or blocking its aqueous pore are non-competitive antagonists. Non-competitive antagonists acting as open channel blockers are therapeutically attractive because of their recognition of over-activated TRPV1 channels, which can reduce the potential of unwanted side effects.[7]
Pharmacophore
The
helices S5 and S6. 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 combined use of a pharmacophore model, assembled from highly optimized TRPV1 antagonists, with a homology model of the protein has enhanced understanding of the observed structure–activity relationships of many series of current TRPV1 antagonists, and should be useful in the discovery of new classes of antagonists.[2]
Structure activity relationship
Figure 3. Structure activity relationship of the capsaicin related compounds oleovanillamine and phenylacetylrivanyl.
Capsaicin (fig. 2) has three functional regions: an aromatic A region where a parent homovanillyl (3-methoxy 4-hydroxybenzyl) group is optimal, a B region known as the ester or amide linker and the aliphatic C region where a lipophilic octanyl moiety is associated with the highest potency. The homovanillyl motif and amide bond regions contain dipolar groups which are implicated in hydrogen bonding interactions.[11]
Phenolic hydroxide and amide
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. Replacement of the medium-sized branched fatty acid of capsaicin with longer fatty acids is damaging for activity,[12] but the presence of unsaturations restores and potentiates activity e.g. oleoylvanillamine (olvanil)(fig. 3a), is 10-fold more potent than capsaicin in TRPV1 activation assays.[13]
1,3-Di(arylalkyl)thioureas
Figure 4. Structure-activity relationship of thiourea derivatives
guaiacyl moiety of capsaicinoids with a 3-fluoro-4-sulfonylamido group found critical to revert activity. This led to the design of C-region moiety mimicked on RTX, led to compound seen in figure 4b, that showed excellent analgesic activity in mice.[18][19] An alternative optimization of the lipophilic C region led to JYL1421 (fig. 4c), another promising clinical candidate.[20]
Di(arylalkyl)- and aryl(arylakyl)ureas
Figure 5. Structure-activity relationship of urea derivatives
Several capsaicin analogs of the urea type were developed by
enzymes and channels[22] whereas the related very potent and specific TRPV1 antagonist A-425619 (fig. 5c) could reduce pain associated with inflammation and tissue injury in rats.[23] Further research has led to a variety of small-molecule antagonists of TRPV1, including the ureas SB-705498 (fig. 5d), SB-452533 (fig. 5e)[16,17] and ABT-102(fig. 5f), compounds that have entered clinical trials.[24]
Cinnamides
Figure 6. Structure-activity relationship of urea derivatives
N-Arylcinnamides have emerged as potent and important class of TRPV1 antagonists, Compound SB-366791, (fig. 6a) shows competitive and specific activity in both human and rat TRPV1 receptors overall profile of receptor selectivity much better than that of capsazepine.[25][26]
Within this series of compounds,
pharmacokinetic profile, boding well for clinical efficacy.[27] Another potent blocker from this group is AMG0347(fig. 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.[28]
Carboxamides
Figure 7. Structure-activity relationship of carboxamide derivatives
Several TRPV1 antagonists of the
heterogenous, as exemplified by comparison of the nicotinamide derivative SB-782443 (fig. 7a), the thiazolylcarboxamide (fig. 7b), and the tetrahydropyridylcarboxamide (fig. 7c).[29] SB-782443 (fig. 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.[30][31] Based on their in vitro profile, several compounds of this class qualified for preclinical development.[29]
Other derivatives
Figure 8. Structure-activity relationship of unclassified derivatives
Nonclassic antagonists lack the urea, thiourea, or amide groups typical of the classic TRPV1 ligands. Two major structural types of nonclassic antagonists have been discovered. First there are the
Janssen, Abbott and Merck pharmaceuticals (fig. 8c) having a 5-aminoisoquinoline group as a common feature suggesting that there is a key interaction of this group at the receptor site for TRPV1 antagonist activity.[33]
Current status
In November 2009, the FDA approved Qutenza (capsaicin, 8% topical patch) for postherpetic neuralgia.[35]
Clinical trials
Figure 9. TRPV1 antagonists in clinical development as of 2009
As of late 2009, available public information suggests that quite a few are in clinical trials. Several biotechnology and pharmaceutical companies are developing TRPV1 ligands and the emphasis seems to be on both agonists and antagonists. Although the agonists appear to be further along in clinical development.[1]
Agonists
NeurogesX has successfully completed three Phase III clinical studies of Qutenza (NGX-4010) that met studies primary endpoints. Qutenza is a synthetic trans-capsaicin and drug delivery is by a rapid-delivery patch application system[36] NeurogesX plans to launch Qutenza in the United States in the first half of November 2010.[37]
Anesiva, another biotechnology company, has completed two Phase III trials of Adlea (ALGRX 4975), an injectable capsaicin. Adlea is promising as a pain reliever[38] and both trials showed that Adlea's safety profile of adverse events, wound healing, and wound sensory function were similar to placebo over the study duration.[39]
Antagonists
At least seven orally active TRPV1 antagonist substances have progressed into clinical development and several more are in preclinical development. The ligand
GlaxoSmithKline, Merck-Neurogen, Amgen, and AstraZeneca are all developing TRPV1 antagonist and all are developing substances that have completed phase I trials successfully.[1]
