133457-89-3

Upstream product

• 31954-27-5 N-(tert-butoxycarbonyl)glycine methyl ester 
• 133457-88-2 ethyl (cyclopropylmethyl)methylphosphinate 

Relevant academic research and scientific papers

Phosphinic acid analogues of GABA. 2. Selective, orally active GABA(B) antagonists

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.

P-subsituted propane-phosphinic acid compounds

Compounds of the formula I STR1 wherein either R1 is halogen, R1 ' is halogen or hydrogen and R2 and R2 ' denote hydrogen or R1 and R1 ' represent hydrogen, R2 is an aliphatic or aromatic radical and R2 ' is hydroxy or R2 and R2 ' together represent oxo, and wherein R denotes an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic radical having 2 or more carbon atoms or, if R1 and R1 ' denote hydrogen, R2 represents an aromatic radical and R2 ' is hydroxy, R represents methyl, and their salts are useful as nootropics, antidepressants and/or anxiolytics. The can be manufacture by replacing any group R5 by hydrogen and/or converting any group Z0 into amino in a compound of formula II STR2 in which R, R1, R1 ', R2 and R2 ' have their previous significances, Z represents a protected or latent amino group Z0 and R4 denotes hydrogen or a hyddroxy-protective group R5, and wherein amino as a constituent of R and/or hydroxy R2 ' or oxo R2 +R2 ' may be present in a temporarily protected form.