ABSTRACT
Structure-activity relationships for the A-region in a series of N-4-t-butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamides as TRPV1 antagonists have been investigated. Among them, the 3-fluoro analogue 54 showed high binding affinity and potent antagonism for both rTRPV1 and hTRPV1 in CHO cells. Its stereospecific activity was demonstrated with marked selectivity for the (S)-configuration (54S versus 54R). A docking study of 54S with our hTRPV1 homology model highlighted crucial hydrogen bonds between the ligand and the receptor contributing to its potency.
Subject(s)
Amides/chemistry , Amides/pharmacology , TRPV Cation Channels/antagonists & inhibitors , Amides/chemical synthesis , Animals , Binding Sites , CHO Cells , Computer Simulation , Cricetinae , Cricetulus , Humans , Hydrogen Bonding , Protein Binding/drug effects , Protein Structure, Tertiary , Rats , Stereoisomerism , Structure-Activity Relationship , TRPV Cation Channels/metabolismABSTRACT
Recently, 1,3-diarylalkyl thioureas have merged as one of the promising nonvanilloid TRPV1 antagonists possessing excellent therapeutic potential in pain regulation. In this paper, the full structure-activity relationship for TRPV1 antagonism of a novel series of 1,3-diarylalky thioureas is reported. Exploration of the structure-activity relationship, by systemically modulating three essential pharmacophoric regions, led to six examples of 1,3-dibenzyl thioureas, which exhibit Ca(2+) uptake inhibition in rat DRG neuron with IC(50) between 10 and 100 nM.
Subject(s)
Ion Channels/antagonists & inhibitors , Thiourea/analogs & derivatives , Thiourea/chemical synthesis , Animals , Animals, Newborn , Calcium/metabolism , Ganglia, Spinal/cytology , In Vitro Techniques , Neurons/drug effects , Neurons/metabolism , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , TRPV Cation Channels , Thiourea/pharmacologyABSTRACT
The structure-activity relationships for the 'A-region' of N-(4-t-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues have been investigated as TRPV1 receptor antagonists. The 2-halogen analogues showed enhanced antagonism compared to the prototype antagonist.
Subject(s)
Sulfonamides/pharmacology , TRPV Cation Channels/antagonists & inhibitors , Thiourea/analogs & derivatives , Thiourea/pharmacology , Animals , CHO Cells , Calcium/metabolism , Cricetinae , Ligands , Molecular Structure , Rats , Structure-Activity Relationship , Sulfonamides/chemistry , TRPV Cation Channels/metabolism , Thiourea/chemistryABSTRACT
In a continuing effort to elucidate the structure-activity relationships of the lead antagonist N-[2-(3,4-dimethylbenzyl)-3-pivaloyloxypropyl]-N'-[4-(methylsulfonylamino)benzyl]thiourea (1), the distances between the proposed four pharmacophores in 1 have been varied by insertion or deletion of one carbon to optimize their fit to the receptor. In addition, the acyloxy group of the C region was replaced with amide and N-hydroxy amide to identify the pharmacophoric importance of the ester group in the C2 region. The results indicated that the pharmacophoric arrangement of 1 was optimal for receptor binding affinity and antagonism, and the ester of the C2 region was significant for receptor binding. Among the derivatives, compound 19 showed distinct behavior with a 2-fold improvement in antagonism but a 13-fold reduction in binding affinity compared to 1. The partial separation of pharmacophoric requirements of these two assays has been noted before and compound 19 is thus selective for the calcium entry-linked receptor population. The conformational analysis of 1 generated three distinct conformers having different types of hydrophobic interactions, which will be utilized for exploring the active conformation of the VR1 ligand.
Subject(s)
Benzyl Compounds/chemistry , Benzyl Compounds/pharmacology , Phenylthiourea/analogs & derivatives , Phenylthiourea/chemistry , Phenylthiourea/pharmacology , Receptors, Drug/antagonists & inhibitors , Thiourea/analogs & derivatives , Thiourea/chemistry , Thiourea/pharmacology , Amides/chemistry , Animals , Benzyl Compounds/chemical synthesis , CHO Cells , Calcium/metabolism , Cricetinae , Ligands , Models, Molecular , Molecular Conformation , Molecular Structure , Phenylthiourea/chemical synthesis , Rats , Receptors, Drug/genetics , Receptors, Drug/metabolism , Structure-Activity Relationship , Thiourea/chemical synthesisABSTRACT
The structural modifications on the B-region of the potent and high affinity vanilloid receptor (VR1) lead ligand N-(3-acyloxy-2-benzylpropyl)-N(')-[4-(methylsulfonylamino)benzyl]thiourea were investigated by the replacement of the thiourea with diverse isosteric functional groups. Structure-activity analysis indicated that the A-region in this series was the primary factor in determining the agonistic/antagonistic activities regardless of the B-region. The N(C)-hydroxy thiourea analogues (12, 13) showed excellent analgesic activities in the acetic acid writhing assay compared to the parent thiourea analogues.