TY - JOUR
T1 - Halogenation of 4-hydroxy/amino-3-methoxyphenyl acetamide TRPV1 agonists showed enhanced antagonism to capsaicin
AU - Kang, Dong Wook
AU - Kim, Yong Soo
AU - Lim, Kwang Su
AU - Kim, Myeong Seop
AU - Pearce, Larry V.
AU - Pavlyukovets, Vladimir A.
AU - Tao, Andy K.
AU - Lang-Kuhs, Krystle A.
AU - Blumberg, Peter M.
AU - Lee, Jeewoo
PY - 2010/11/15
Y1 - 2010/11/15
N2 - As an extension of our analysis of the effect of halogenation on thiourea TRPV1 agonists, we have now modified selected 4-hydroxy(or 4-amino)-3- methoxyphenyl acetamide TRPV1 agonists by 5- or 6-halogenation on the aromatic A-region and evaluated them for potency for TRPV1 binding and regulation and for their pattern of agonism/antagonism (efficacy). Halogenation shifted the functional activity at TRPV1 toward antagonism with a greater extent of antagonism as the size of the halogen increased (I > Br > Cl), as previously observed for the thiourea series. The extent of antagonism was greater for halogenation at the 5-position than at the 6-position, in contrast to SAR for the thiourea series. In this series, compounds 55 and 75 showed the most potent antagonism, with Ki (ant) = 2.77 and 2.19 nM, respectively, on rTRPV1 expressed in Chinese hamster ovary cells. The compounds were thus ca. 40-60-fold more potent than 6′-iodononivamide.
AB - As an extension of our analysis of the effect of halogenation on thiourea TRPV1 agonists, we have now modified selected 4-hydroxy(or 4-amino)-3- methoxyphenyl acetamide TRPV1 agonists by 5- or 6-halogenation on the aromatic A-region and evaluated them for potency for TRPV1 binding and regulation and for their pattern of agonism/antagonism (efficacy). Halogenation shifted the functional activity at TRPV1 toward antagonism with a greater extent of antagonism as the size of the halogen increased (I > Br > Cl), as previously observed for the thiourea series. The extent of antagonism was greater for halogenation at the 5-position than at the 6-position, in contrast to SAR for the thiourea series. In this series, compounds 55 and 75 showed the most potent antagonism, with Ki (ant) = 2.77 and 2.19 nM, respectively, on rTRPV1 expressed in Chinese hamster ovary cells. The compounds were thus ca. 40-60-fold more potent than 6′-iodononivamide.
KW - Capsaicin
KW - Capsaicinoid
KW - Halogenation
KW - Resiniferatoxin
KW - TRPV1 agonist
KW - TRPV1 antagonist
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U2 - 10.1016/j.bmc.2010.09.001
DO - 10.1016/j.bmc.2010.09.001
M3 - Article
C2 - 20937561
AN - SCOPUS:78449263017
SN - 0968-0896
VL - 18
SP - 8092
EP - 8105
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 22
ER -