Solid-phase synthesis and pharmacological evaluation of analogues of PhTX-12-A potent and selective nicotinic acetylcholine receptor antagonist
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Solid-phase synthesis and pharmacological evaluation of analogues of PhTX-12-A potent and selective nicotinic acetylcholine receptor antagonist. / Strømgaard, Kristian; Mellor, Ian R; Andersen, Kim; Neagoe, Ioana; Pluteanu, Florentina; Usherwood, Peter N R; Krogsgaard-Larsen, Povl; Jaroszewski, Jerzy W.
In: Bioorganic & Medicinal Chemistry Letters, Vol. 12, No. 8, 22.04.2002, p. 1159-1162.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Solid-phase synthesis and pharmacological evaluation of analogues of PhTX-12-A potent and selective nicotinic acetylcholine receptor antagonist
AU - Strømgaard, Kristian
AU - Mellor, Ian R
AU - Andersen, Kim
AU - Neagoe, Ioana
AU - Pluteanu, Florentina
AU - Usherwood, Peter N R
AU - Krogsgaard-Larsen, Povl
AU - Jaroszewski, Jerzy W
PY - 2002/4/22
Y1 - 2002/4/22
N2 - Philanthotoxin-12 (PhTX-12) is a novel potent and selective, noncompetitive antagonist of nicotinic acetylcholine receptors (nAChRs). Homologues of PhTX-12 with 7-11 methylene groups between the primary amino group and the aromatic head-group were synthesized using solid-phase methodology. In vitro electrophysiological studies of nAChR demonstrated that decreasing the number of methylene groups from 12 to 11 significantly increased potency. Antagonism by PhTX-11, like that of PhTX-12, was only weakly voltage-dependent. When the methylene spacer was reduced further, antagonism was decreased below that of PhTX-12, and in some cases potentiation of ACh responses by up to 60% was observed.
AB - Philanthotoxin-12 (PhTX-12) is a novel potent and selective, noncompetitive antagonist of nicotinic acetylcholine receptors (nAChRs). Homologues of PhTX-12 with 7-11 methylene groups between the primary amino group and the aromatic head-group were synthesized using solid-phase methodology. In vitro electrophysiological studies of nAChR demonstrated that decreasing the number of methylene groups from 12 to 11 significantly increased potency. Antagonism by PhTX-11, like that of PhTX-12, was only weakly voltage-dependent. When the methylene spacer was reduced further, antagonism was decreased below that of PhTX-12, and in some cases potentiation of ACh responses by up to 60% was observed.
KW - Chromatography, High Pressure Liquid
KW - Drug Evaluation, Preclinical
KW - Mass Spectrometry
KW - Nicotinic Antagonists
KW - Patch-Clamp Techniques
KW - Polyamines
KW - Tyrosine
M3 - Journal article
C2 - 11934578
VL - 12
SP - 1159
EP - 1162
JO - Bioorganic & Medicinal Chemistry Letters
JF - Bioorganic & Medicinal Chemistry Letters
SN - 0960-894X
IS - 8
ER -
ID: 45823749