1489-76-5Relevant articles and documents
Ligands for expression cloning and isolation of GABAB receptors
Froestl, Wolfgang,Bettler, Bernhard,Bittiger, Helmut,Heid, Jakob,Kaupmann, Klemens,Mickel, Stuart J.,Strub, Dietrich
, p. 173 - 183 (2003)
The scope of the plenary lecture at the occasion of the Xth Meeting on Heterocyclic Structures in Medicinal Chemistry, Palermo 2002, is considerably larger than that of the main lecture at the XVIth International Symposium on Medicinal Chemistry, Bologna 2000, described by Froestl et al. in Farmaco 56 (2001) 101. Additional information is presented, in particular, on the reaction conditions for the 31 step synthesis of the combined affinity chromatography and photoaffinity radioligand [125I]CGP84963 and on the recent developments of the molecular biology of GABAB receptors.
Methotrexate Analogues. 29. Effect of γ-Aminobutyric Acid Spacers between the Pteroyl and Glutamate Moieties on Enzyme Binding and Cell Growth Inhibition
Rosowsky, Andre,Forsch, Ronald A.,Freisheim, James H.,Danenberg, Peter V.,Moran, Richard G.,Wick, Michael M.
, p. 1872 - 1876 (2007/10/02)
A series of "stretched" methotrexate (MTX) analogues containing up to five 4-aminobutyryl (Gab) spacers between the 4-amino-4-deoxy-N10-methylpteroyl (MeAPA) moiety and the glutamate (Glu) side chain was prepared.Interest in these compounds stemmed from their relationship to MTX γ-polyglutamates, from which they differ only in lacking "internal" α-carboxyl groups.The ability of the MeAPA-Gabn-Glu derivatives to inhibit dihydrofolate reductase (DHFR) and thymidylate synthase (TS) in vitro and to inhibit the growth of tumor cells in culture was evaluated.The IC50 for DHFR inhibition increased progressively from 0.082 to 0.84 μM as the number of Gab spacers was varied from one to five.At the same time the introduction of Gab spacers was found to produce substantial TS inhibition (Ki 0.1-0.4 μM) similar to that reported for MTX polyglutamates.Despite the activity of the MeAPA-Gabn-Glu derivatives as combined inhibitors of TS and DHFR, there was a steep loss of cell growth inhibitory potency as the number of Gab spacers was increased.This most likely reflects low cell uptake and the fact that when n > 1 there is almost total abolition of substrate activity for folypolyglutamate synthetase, which had previously been observed with n = 1.
