title: N-[4-(methylsulfonylamino)benzyl]thiourea analogues as vanilloid receptor antagonists: analysis of structure-activity relationships for the "C-Region".
abstract: We recently reported that N-(4-t-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl] thiourea (2) was a high affinity antagonist of the vanilloid receptor with a binding affinity of K(i)=63 nM and an antagonism of K(i)=53.9 nM in rat VR1 heterologously expressed in Chinese hamster ovary (CHO) cells (Mol. Pharmacol. 2002, 62, 947-956). In an effort to further improve binding affinity and antagonistic potency, we have modified the C-region of the lead 4-t-butylbenzyl group with diverse surrogates, such as araalkyl, alkyl, 4-alkynylbenzyl, indanyl, 3,3-diarylpropyl, 4-alkoxybenzyl, 4-substituted piperazine and piperidine. The lipophilic surrogates, arylalkyl and alkyl, conferred modest decreases in binding affinities and antagonistic potencies; the groups having heteroatoms resulted in dramatic decreases. Our findings indicate that 4-t-butylbenzyl is one of the most favorable groups for high receptor binding and potent antagonism to VR1 in this structural series.
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: Sang-Uk
authors.initials: SU
authors.lastname: Kang
authors.forename: Ju-Ok
authors.initials: JO
authors.lastname: Lim
authors.forename: Hyun-Kyung
authors.initials: HK
authors.lastname: Choi
authors.forename: Mi-kyung
authors.initials: MK
authors.lastname: Jin
authors.forename: Attila
authors.initials: A
authors.lastname: Toth
authors.forename: Larry V
authors.initials: LV
authors.lastname: Pearce
authors.forename: Richard
authors.initials: R
authors.lastname: Tran
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Tamas
authors.initials: T
authors.lastname: Szabo
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
mesh_terms: D000818:Animals; D001671:Biochemistry / Q000379:methods; D016466:CHO Cells; D002211:Capsaicin / Q000494:pharmacology; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical / Q000379:methods; D051381:Rats; D011955:Receptors, Drug / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives*
chemical_list: D011955:Receptors, Drug; D013890:Thiourea; D002211:Capsaicin