Search results for "Phosphinic Acids"
showing 9 items of 9 documents
TRPM8 Channel Activation Reduces the Spontaneous Contractions in Human Distal Colon
2020
The transient receptor potential-melastatin 8 (TRPM8) is a non-selective Ca2+-permeable channel, activated by cold, membrane depolarization, and different cooling compounds. TRPM8 expression has been found in gut mucosal, submucosal, and muscular nerve endings. Although TRPM8 plays a role in pathological conditions, being involved in visceral pain and inflammation, the physiological functions in the digestive system remain unclear as yet. The aims of the present study were: (i) to verify the TRPM8 expression in human distal colon
Synthesis and activity of phosphinic tripeptide inhibitors of cathepsin C
2004
Phosphinic tripeptide analogues Gly-Xaaψ[P(O)(OH)CH2]-Gly have been developed as inhibitors of cathepsin C (DPP I), a lysosomal, papain-like cysteine protease. The target compounds were synthesised by addition of methyl acrylate to the appropriate phosphinic acids followed by the N-terminus elongation using mixed anhydride procedure. The latter step has been demonstrated to be a suitable method for N-terminal extension of the phosphinic pseudopeptide analogues without requirement of hydroxyphosphinyl protection. The title compounds appeared to be moderate inhibitors of the cathepsin C. However, although designed as transition state analogues, they surprisingly exhibited noncompetitive mode …
Functional evidence for GABA as modulator of the contractility of the longitudinal muscle in mouse duodenum: Role of GABAA and GABAC receptors
2007
We investigated, in vitro, the effects of gamma-aminobutyric acid (GABA) on the spontaneous mechanical activity of the longitudinal smooth muscle in mouse duodenum. GABA induced an excitatory effect, consisting in an increase in the basal tone, which was antagonized by the GABA(A)-receptor antagonist, bicuculline, potentiated by (1,2,5,6-Tetrahydropyridin-4-yl)methylphosphinic acid hydrate (TPMPA), a GABA(C)-receptor antagonist and it was not affected by phaclofen, a GABA(B)-receptor antagonist. Muscimol, GABA(A) receptor agonist, induced a contractile effect markedly reduced by bicuculline, tetrodotoxin (TTX), hexamethonium and atropine. Cis-4-aminocrotonic acid (CACA), a specific GABA(C) …
Short-term adaptation of conditioned fear responses through endocannabinoid signaling in the central amygdala
2010
International audience; Both, the cannabinoid receptor type 1 (CB1) and the central nucleus of the amygdala (CeA) are known to play crucial roles in the processing of fear and anxiety, whereby they appear to be especially involved in the control of fear states. However, in contrast to many other brain regions including the cortical subregions of the amygdala, the existence of CB1 in the CeA remains enigmatic. Here we show that CB1 is expressed in the CeA of mice and that CB1 in the CeA mediates short-term synaptic plasticity, namely depolarization-induced suppression of excitation (DSE) and inhibition (DSI). Moreover, the CB1 antagonist AM251 increased both excitatory and inhibitory postsyn…
A synthetic method for diversification of the P1′ substituent in phosphinic dipeptides as a tool for exploration of the specificity of the S1′ bindin…
2007
Abstract A novel, general, and versatile method of diversification of the P1′ position in phosphinic pseudodipeptides, presumable inhibitors of proteolytic enzymes, was elaborated. The procedure was based on parallel derivatization of the amino group in the suitably protected phosphinate building blocks with appropriate alkyl and aryl halides. This synthetic strategy represents an original approach to phosphinic dipeptide chemistry. Its usefulness was confirmed by obtaining a series of P1′ modified phosphinic dipeptides, inhibitors of cytosolic leucine aminopeptidase, through computer-aided design basing on the structure of homophenylalanyl-phenylalanine analogue (hPheP[CH 2 ]Phe) bound in …
A structural insight into the P1 S1 binding mode of diaminoethylphosphonic and phosphinic acids, selective inhibitors of alanine aminopeptidases
2016
Abstract N′-substituted 1,2-diaminoethylphosphonic acids and 1,2-diaminoethylphosphinic dipeptides were explored to unveil the structural context of the unexpected selectivity of these inhibitors of M1 alanine aminopeptidases (APNs) versus M17 leucine aminopeptidase (LAP). The diaminophosphonic acids were obtained via aziridines in an improved synthetic procedure that was further expanded for the phosphinic pseudodipeptide system. The inhibitory activity, measured for three M1 and one M17 metalloaminopeptidases of different sources (bacterial, human and porcine), revealed several potent compounds (e.g., K i = 65 nM of 1u for Hs APN). Two structures of an M1 representative (APN from Neisser…
GABAC receptors are functionally expressed in the intermediate zone and regulate radial migration in the embryonic mouse neocortex
2010
Radial neuronal migration in the cerebral cortex depends on trophic factors and the activation of different voltage- and ligand-gated channels. To examine the func- tional role of GABAC receptors in radial migration we ana- lyzed the effects of specific GABAA and GABAC receptor antagonists on the migration of BrdU-labeled neurons in vitro using organotypic neocortical slice cultures. These experi- ments revealed that the GABAA specific inhibitor bicuculline methiodide facilitated neuronal migration, while the GABAC specific inhibitor (1,2,5,6-tetrahydropyridine-4-yl) methylphos- phinic-acid (TPMPA) impeded migration. Co-application of TPMPA and bicuculline methiodide or the unspecific ionot…
Individual stereoisomers of phosphinic dipeptide inhibitor of leucine aminopeptidase
2008
Abstract Individual stereoisomers of the phosphinic pseudodipeptide hPheψ[P(O)(OH)CH2]Phe were obtained by stereoselective liquid chromatographic separation as N- and C-terminally protected derivative on quinidine carbamate modified silica stationary phase. The stereoisomeric purity, exceeding 95% for each fraction, was determined before and after deprotection using two independent methods. The absolute configuration was rationally assigned by application of enantiomerically pure phosphinic acid substrates in the synthetic procedure and correlation with biological activity of the products. Substantial differences in inhibition of leucine aminopeptidase by the individual isomers revealed nov…
Enantiodifferentiation of N-benzyloxycarbonylaminophosphonic and phosphinic acids and their esters using cyclodextrins by means of capillary electrop…
2005
Capillary electrophoresis was successfully applied for separation of the enantiomers of N-benzyloxycarbonyl-alpha-aminophosphonic and alpha-aminophosphinic acids as well as their ethyl and phenyl monoesters with the use of a range of commercially available cyclodextrins (alpha, beta and hydroxypropyl-gamma-cyclodextrins) as chiral selectors. The dependence of effectiveness of separation on type and concentration of these chiral selectors as well as on pH of background electrolyte was examined in some detail.