Solid-phase synthesis and pharmacological evaluation of analogues of PhTX-12-A potent and selective nicotinic acetylcholine receptor antagonist.
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.
Strømgaard
Kristian
K
Department of Medicinal Chemistry and NeuroScience PharmaBiotec Research Center, Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100, Copenhagen, Denmark. krst@chem.columbia.edu
Mellor
Ian R
IR
Andersen
Kim
K
Neagoe
Ioana
I
Pluteanu
Florentina
F
Usherwood
Peter N R
PN
Krogsgaard-Larsen
Povl
P
Jaroszewski
Jerzy W
JW
D002851:Chromatography, High Pressure Liquid; D004353:Drug Evaluation, Preclinical; D013058:Mass Spectrometry; D018733:Nicotinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011073:Polyamines; D014443:Tyrosine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D018733:Nicotinic Antagonists; D011073:Polyamines; C405122:phTX 12; D014443:Tyrosine