title: Analysis of structure-activity relationships with the N-(3-acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea template for vanilloid receptor 1 antagonism.
abstract: 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.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, South Korea. jeewoo@snu.ac.kr
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
authors.forename: Su Yeon
authors.initials: SY
authors.lastname: Kim
authors.forename: Jiyoun
authors.initials: J
authors.lastname: Lee
authors.forename: Myungsim
authors.initials: M
authors.lastname: Kang
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Kil
authors.forename: Hyun-Kyung
authors.initials: HK
authors.lastname: Choi
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Jin
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Attila
authors.initials: A
authors.lastname: Toth
authors.forename: Larry V
authors.initials: LV
authors.lastname: Pearce
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lundberg
authors.forename: Richard
authors.initials: R
authors.lastname: Tran
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010670:Phenylthiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D011955:Receptors, Drug / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000577:Amides; D001593:Benzyl Compounds; D008024:Ligands; C494909:N-(3-acyloxy-2-benzylpropyl)-N'-(4-(methylsulfonylamino)benzyl)thiourea; D011955:Receptors, Drug; D010670:Phenylthiourea; D013890:Thiourea; C037877:benzylthiourea; D002118:Calcium