RESUMEN

The influence of 2-amino-3-phosphonopropionic acid (AP3), an antagonist of metabotropic glutamate receptors and its N-methyl analog (N-methyl AP3) on acquisition, consolidation and recall of information in a passive avoidance situation was tested. Both compounds improved three examined parameters. The significant effect of AP3 appeared at the icv dose of 12.5 micrograms per rat when its influence on acquisition and consolidation was tested, and at the icv dose of 100 micrograms when its influence on retrieval process was evaluated. The significant improvement of acquisition of information was observed at the icv dose of 50 micrograms per rat of N-methyl AP3, but significant facilitation of consolidation and retrieval processes appeared at the higher dose of 100 micrograms per rat. Significant improvement of performance in a passive avoidance situation persisted in all experiments to the highest used dose of both compounds, 250 micrograms.

Asunto(s)

RESUMEN

The influence of 2-amino-3-phosphonopropionic acid (AP3) an antagonist of metabotropic glutamate receptors and its N-methyl analog (N-methyl AP3) on locomotor activity in the "open field" test, apomorphine stereotypy and haloperidol catalepsy were tested. Both compounds had not any influence on spontaneous crossings of squares, number of rearings and bar approaches in the "open field" test. AP3 and its N-methyl analog significantly enhanced apomorphine stereotypy at the intracerebroventricular (icv) doses of 100 and 200 micrograms per rat respectively. Although, both compounds significantly diminished haloperidol catalepsy at the icv doses of 50, 100 and 200 micrograms per rat. All observed effects of AP3 and N-methyl AP3 were dose independent. Methyl substitution at the N-position in AP3 did not change pharmacological properties of this compound i.e. its influence on behavior mainly dependent on dopaminergic systems.

Asunto(s)

RESUMEN

A series of dipeptides containing N-terminal alanine or leucine and a wide range of P-terminal racemic 1-amino-alkanephosphonates were prepared and tested in vitro for their ability to inhibit the growth of various bacterial species. The results demonstrate that peptides containing 4-amino-4-phosphonobutyric acid and 1-amino-1-methylethanephosphonic acid exhibit antibacterial activity comparable with that observed in the case of peptides containing P-terminal racemic 1-aminoethanephosphonic acid (analogue of alanine) used as a positive control.

Asunto(s)

RESUMEN

Ten newly synthesized derivatives of phosphonoamino acids were subjected to preliminary pharmacological evaluation in mice and rats. We investigated their effect on acute toxicity, body temperature, spontaneous and exploratory activity, electrogenic and pentetrazole convulsions, and motor coordination and gamma-amino-butyric acid concentration in various brain regions. The most active derivatives were alpha-amino-alpha-p-hydroxyphenyl-methylphosphonic acid 40, beta-(alpha-aminoethyl)-carbamoyl-ethylphosphonic acid 43, alpha-amino-beta-phenylethylphosphonic acid 46, and alpha-amino-beta-(p-nitrophenyl)-ethylphosphonic acid 47. Those compounds depressed the spontaneous locomotor activity and displayed protective action in electrogenic and pentetrazole convulsions.

Asunto(s)

RESUMEN

Michaelis-Arbuzov reaction of N-(chloroacetyl)amino phosphonic acids or their esters, followed by acidolysis, gives moderate yields of N-(phosphonoacetyl) derivatives of a variety of (aminoalkyl)phosphonic acids, including analogues of the cytostatic agent PALA, in which the alpha- or beta-carboxylic groups in the aspartate moiety are replaced by a PO3H2 function. Assay of cytostatic activity with human KB cell lines indicates that the substitution of any of the COOH groups in PALA with PO3H2 results in total loss of cytostatic activity. No activity was observed also in the case of other [N-(phosphonoacetyl)amino]alkylphosphonic acids described in this report.

Asunto(s)

RESUMEN

Central pharmacological properties of 38 aminophosphonic acids and their derivatives, mostly newly synthesized, were investigated on mice and rats. Acute toxicity, neurotoxic activity, influence on spontaneous locomotor activity, body temperature, electrogenic and pentetrazol convulsions, on cerebral GABA level were tested. The most active compounds were (in a decreasing order of activity): 2-amino-7-phosphonoheptanoic, 2-amino-5-phosphonovaleric, 2-amino-8-phosphonooctanoic, 2-amino-2-methyl-3-methylphosphonopropionic, and 3-amino-3-hydroxy-5-phosphonovaleric acid.

Asunto(s)

RESUMEN

L(-)-, and D(+)-enantiomers of 1-amino-2-phenylethylphosphonic acid (PheP), a phosphonic analogue of phenylalanine, inhibit the activity of L-phenylalanine ammonia-lyase (EC 4.3.1.5) of potato tuber tissue in vitro. The apparent type of inhibition depends on concentration of PheP; as the concentration of D-PheP is raised from 10(-5) M to 2.5 X 10(-3) M, the type of inhibition shifts from competitive through mixed and non-competitive to uncompetitive. L-PheP exerts either a competitive or mixed-type inhibition at low (10(-6)-10(-5) M) or moderate (5 X 10(-5)-2 X 10(-4) M) concentration. Ki for the concentration range of competitive inhibition were 6.5 X 10(-6) M, 5.3 X 10(-5)M and 1.6 X 10(-5) M for L-, D-, and D,L-PheP, respectively. These Ki values are valid for a relatively narrow range of L-Phe concentration (0.2-4 mM) as L-phenylalanine ammonia-lyase does not follow the Michaelis-Menten kinetics of the reaction.

Asunto(s)

RESUMEN

Cytostatic activity of 48 new amino acid analogs and derivatives of phosphonic acid type was tested against KB cell line in vitro. The tests were performed according to the recommended international protocol for screening of chemical agents against tissue culture system. Three of the compounds tested: No. No, 29, 33 and 32 revealed cytostatic activity at the concentrations: 63, 150, and 180 micrograms ml-1 respectively (ID50).

Asunto(s)

RESUMEN

Four analogues of aspartame (aspartylphenylalanine methyl ester) were prepared in which one of the carboxylate groups was replaced by a phosphonate group. None of the peptides so obtained was sweet, in contrast with the parent compound which is over 100 times sweeter than sucrose. These results contrast with several published reports of phosphonate analogues of amino acids and peptides which are potent inhibitors of enzymes containing acceptor sites for the parent compound.

Asunto(s)

RESUMEN

Eight analogs of enkephalins containing the phosphonic analogs of Gly, Leu, Met, Phe and Pro have been synthesized by standard procedures in solution. The key intermediates in the synthesis were pure diastereomers of dialkyl N-L-phenylalanyl/aminoalkanephosphonates obtained from racemic dialkyl aminoalkanephosphonates by coupling with phenylalanine and resolution of the resulting mixture of L, D and L, L dipeptides by means of column chromatography.

Asunto(s)

Asunto(s)

Asunto(s)

RESUMEN

Rabbit muscle pyruvate kinase activity has been studied in the presence of L-phenylalanine and its analogs: L-phenylalanyl methyl ester (PheOMe), L-1-amino-2-phenylethyl phosphonic acid (PnPhe), L-alanine and L-1-aminoethyl phosphonic acid (PnAla). At appropriate pH and substrate concentrations all the analogs and Phe exhibited activatory and inhibitory effects at low (1--5 mM) and at high (above 5mM) ligand concentrations respectively. Activation of pyruvate kinase by Phe and PheOMe was observed at pH above 8.2 in the presence of 2.5 mM ADP and 0.5 mM phosphoenolpyruvate (P-pyruvate), while PnPhe activation was also observed at pH 7.5. The activatory effect followed the order: PnPhe much greater than Phe greater than PheOMe. All the effectors showed a mixed type of inhibition or activation with P-pyruvate as a variable substrate and a non-competitive inhibition or activation with ADP as a variable substrate.

Asunto(s)

RESUMEN

Cytostatic activity of 18 new phosphonic acid derivatives of cycloleucine, aspartic acid and glutamic acid was tested against human KB and mouse L1210s leukemia cell lines in vitro. The tests were performed according to international protocol 1.600 for screening of chemical agents against tissue culture system. Four of the tested compounds revealed their cytostatic activity at the dose 10 micrograms/ml.

Asunto(s)

Asunto(s)

Asunto(s)

Asunto(s)

Asunto(s)