Solid-phase synthesis and pharmacological evaluation of analogues of PhTX-12-A potent and selective nicotinic acetylcholine receptor antagonist

Kristian Strømgaard; Ian R Mellor; Kim Andersen; Ioana Neagoe; Florentina Pluteanu; Peter N R Usherwood; Povl Krogsgaard-Larsen; Jerzy W Jaroszewski

Solid-phase synthesis and pharmacological evaluation of analogues of PhTX-12-A potent and selective nicotinic acetylcholine receptor antagonist

Kristian Strømgaard, Ian R Mellor, Kim Andersen, Ioana Neagoe, Florentina Pluteanu, Peter N R Usherwood, Povl Krogsgaard-Larsen, Jerzy W Jaroszewski

22 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	12
Issue number	8
Pages (from-to)	1159-1162
Number of pages	4
ISSN	0960-894X
Publication status	Published - 22 Apr 2002

Keywords

Chromatography, High Pressure Liquid
Drug Evaluation, Preclinical
Mass Spectrometry
Nicotinic Antagonists
Patch-Clamp Techniques
Polyamines
Tyrosine

Cite this

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 et al.

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

@article{bde62c7d4aab4bd6839d84bb4e595d2c,

title = "Solid-phase synthesis and pharmacological evaluation of analogues of PhTX-12-A potent and selective nicotinic acetylcholine receptor antagonist",

abstract = "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.",

keywords = "Chromatography, High Pressure Liquid, Drug Evaluation, Preclinical, Mass Spectrometry, Nicotinic Antagonists, Patch-Clamp Techniques, Polyamines, Tyrosine",

author = "Kristian Str{\o}mgaard and Mellor, {Ian R} and Kim Andersen and Ioana Neagoe and Florentina Pluteanu and Usherwood, {Peter N R} and Povl Krogsgaard-Larsen and Jaroszewski, {Jerzy W}",

year = "2002",

month = apr,

day = "22",

language = "English",

volume = "12",

pages = "1159--1162",

journal = "Bioorganic & Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Pergamon Press",

number = "8",

}

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

SN - 0960-894X

VL - 12

SP - 1159

EP - 1162

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 8

ER -

Solid-phase synthesis and pharmacological evaluation of analogues of PhTX-12-A potent and selective nicotinic acetylcholine receptor antagonist

Abstract

Keywords

Fingerprint

Cite this