N-[4-(methylsulfonylamino)benzyl]thiourea analogues as vanilloid receptor antagonists: analysis of structure-activity relationships for the "C-Region".
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.
Lee
Jeewoo
J
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, South Korea. jeewoo@snu.ac.kr
Kang
Sang-Uk
SU
Lim
Ju-Ok
JO
Choi
Hyun-Kyung
HK
Jin
Mi-kyung
MK
Toth
Attila
A
Pearce
Larry V
LV
Tran
Richard
R
Wang
Yun
Y
Szabo
Tamas
T
Blumberg
Peter M
PM
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*
D011955:Receptors, Drug; D013890:Thiourea; D002211:Capsaicin