Stereospecific High-affinity TRPV1 Antagonists: Chiral N-(2-Benzyl-3-pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl]propionamide Analogues

Abstract

Previously, we reported the thiourea antagonists 2a and 2b as potent and high affinity TRPV1 antagonists. For further optimization of the lead compounds, a series of their amide and alpha-substituted amide surrogates were investigated and novel chiral N-(2-benzyl-3-pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl]propionamide analogues were characterized as potent and stereospecific rTRPV1 antagonists. In particular, compounds 72 and 73 displayed high binding affinities, with K i values of 4.12 and 1.83 nM and potent antagonism with K i values of 0.58 and 5.2 nM, respectively, in rTRPV1/CHO cells. These values are comparable or more potent than those of 5-iodoRTX under the same assay conditions. A distinctive binding model that includes two hydrophobic pockets is proposed for this series of compounds based on docking studies of 57 and 72 with a homology model of the TM3/4 region of TRPV1.

Structure-Activity Relationship of Capsaicin Analogs and Transient Receptor Potential Vanilloid 1-Mediated Human Lung Epithelial Cell Toxicity

“…In this pose, the oxygen atom of the 4-OH moiety was predicted to hydrogen-bond with the hydrogen on the imidazole nitrogen of Trp549 (distance 1.9 Å), and the hydrogen on the amide nitrogen of nonivamide was predicted to hydrogen-bond with the carboxylate group of Glu513 (2.3 Å). The alkyl terminus of nonivamide was localized ϳ2.4 Å from the phenol ring of Tyr511 where hydrophobic interactions probably occur and the 3-MeO group was localized in the hydrophobic "hole-A" pocket composed of Trp549, Met552, Leu553, and likely Phe516 and Leu521, as identified by Ryu et al (2008). This "network" of bonding is consistent with a mechanism of activation for TRPV1 by capsaicinoids whereby the ligand acts as a "molecular tether" between TM3 and TM4 that induces a change in protein structure and/or protein dynamics that ultimately translate into pore opening.…”

“…However, if the alkyl terminus of the dihydroxy analog was lengthened, perhaps TRPV1 would be more potently activated, as suggested by studies with arvanil, linvanil, anandamide, and the arachidonic acid esters of acetaminophen (AM404) (Högestä tt et al, 2005) and dopamine (Huang et al, 2002). The removal of the 3-MeO group in the TRPV1 antagonist capsazepine and constraint of the A/B region (Walpole et al, 1994), as well as increased potency of N-(2-benzyl-3-pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl]propionamide antagonist analogs by the addition of a 4-tert-butyl group to the 2-phenylproionate moiety (Ryu et al, 2008), also support the importance of the 3-MeO and amide groups in TRPV1 activation by agonists. Finally, N-benzylnonanamide (Fig.…”

“…However, the 3,4-dihydroxy catechol analogs of capsaicin exhibited approximately equal potency to the 3-MeO-4-OH cognates in vitro using calcium flux assays, but were less potent in animal-based analgesia models. Finally, site-directed mutagenesis studies of TRPV1 to identify species-specific determinants of differential sensitivity to capsaicin and resiniferatoxin and molecular modeling of the capsaicin binding region have identified amino acid residues and structural features important for binding and activation including Tyr511, Ser512, Met547 (in rat), Trp549, Thr550, Met 552, and Leu553 and a hydrophobic pocket composed of Trp549, Met552, and Leu553 (Jordt and Julius, 2002;Gavva et al, 2004;Ryu et al, 2008). These studies generally concur with the chemical features identified by Walpole et al (1993a,b,c) and have facilitated efforts to design more potent and selective TRPV1 agonists and antagonists.…”

N-4-t-Butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamide TRPV1 antagonists: Structure–activity relationships in the A-region

“…3-Methyl 70 was synthesized from 3-bromo 56 using tetramethyltin with palladium catalyst. The compounds 53 and 71 were prepared from the corresponding acids previously reported 18 by the coupling reaction.…”

“…The two enantiomers of 54 , 54 S and 54 R , were synthesized from the corresponding optically pure acids, prepared by the resolution method using L-phenylalanol, 18 by the above coupling method.…”