139668-46-5Relevant academic research and scientific papers
Phosphinic acid analogues of GABA. 2. Selective, orally active GABA(B) antagonists
Froestl,Mickel,Von Sprecher,Diel,Hall,Maier,Strub,Melillo,Baumann,Bernasconi,Gentsch,Hauser,Jaekel,Karlsson,Klebs,Maitre,Marescaux,Pozza,Schmutz,et al.
, p. 3313 - 3331 (2007/10/02)
In 1987, 25 years after the synthesis of the potent and selective GABA(B) agonist baclofen (1), Kerr et al. described the first GABA(B) antagonist phaclofen 2. However, phaclofen and structurally similar derivatives 3-5 did not cross the blood-brain barrier and hence were inactive in vivo as central nervous system agents. As a consequence, the therapeutic potential of GABA(B) antagonists remained unclear. In exploring GABA and baclofen derivatives by replacing the carboxylic acid residue with various phosphinic acid groups, we discovered more potent and water soluble GABA(B) antagonists. Electrophysiological experiments in vivo demonstrated that some of the new compounds were capable of penetrating the blood-brain barrier after oral administration. Neurotransmitter release experiments showed that they interacted with several presynaptic GABA(B) receptor subtypes, enhancing the release of GABA, glutamate, aspartate, and somatostatin. The new GABA(B) antagonists interacted also with postsynaptic GABA(B) receptors, as they blocked late inhibitory postsynaptic potentials. They facilitated the induction of long-term potentiation in vitro and in vivo, suggesting potential cognition enhancing effects. Fifteen compounds were investigated in various memory and learning paradigms in rodents. Although several compounds were found to be active, only 10 reversed the age-related deficits of old rats in a multiple-trial one-way active avoidance test after chronic treatment. The cognition facilitating effects of 10 were confirmed in learning experiments in Rhesus monkeys. The novel GABA(B) antagonists showed also protective effects in various animal models of absence epilepsy.
Aminoalkanephosphinic acids and salts thereof
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, (2008/06/13)
Novel compounds of formula I STR1 wherein R is selected from butyl, diethoxymethyl, cyclohexylmethyl, cyclohex-3-enylmethyl, benzyl, 4-chlorobenzyl, 4-methylbenzyl and 4-methoxybenzyl, R1 is selected from hydrogen and hydroxy, R2 is
N-aralkyl- and N-heteroaralkyl-aminoalkanephosphinic acids
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, (2008/06/13)
N-aralkyl- and N-heteroaralkyl-aminoalkanephosphinic acids of formula I STR1 wherein R is an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, araliphatic or heteroarylaliphatic radical having at least 2 carbon atoms, R1 is hydrogen or hydroxy, R2 is an araliphatic or heteroarylaliphatic radical substituted by free or functionally modified carboxy that is bonded directly or by way of a spacer, and R3 is hydrogen, lower alkyl or a group R2, and the salts thereof have valuable nootropic and anti-epileptic properties and can be used in the preparation of a nootropic or anti-epileptic medicament.
