MTPG

Blockade of alpha2-adrenergic or metabotropic glutamate receptors induces glutamate release in the locus coeruleus to activate descending inhibition in rats with chronic neuropathic hypersensitivity.[Pubmed:29627342]

Neurosci Lett. 2018 May 29;676:41-45.

Locus coeruleus (LC)-spinal noradrenergic projections are important to endogenous analgesic mechanisms and can be activated by local glutamate signaling in the LC. The current study examined the local glutamatergic, GABAergic, and noradrenergic influences on glutamate release in the LC and noradrenergic descending inhibition in rats 6 weeks after spinal nerve ligation (SNL). Intra-LC injection of the alpha2 adrenoceptor antagonist idazoxan or the group 2 metabotropic glutamate receptor (mGluR) antagonist (RS)-alpha-Methyl-4-tetrazolylphenylglycine (MTPG) increased withdrawal thresholds in SNL animals and this was reversed by the blockade of alpha-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid (AMPA) receptors in the LC or alpha2-adrenoceptors in the spinal cord, but not in normal animals. Neither blockade of GABA-A nor GABA-B receptors in the LC affected withdrawal thresholds in normal and SNL animals. Intra-LC perfusion of idazoxan increased extracellular glutamate in the LC in SNL animals but not in normal animals. Intra-LC perfusion of MTPG increased extracellular glutamate in the LC in both normal and SNL animals. These results suggest that local noradrenaline and glutamate tonically inhibit glutamate release in the LC after peripheral nerve injury and this may contribute to reduced descending inhibition in response to noxious input during chronic neuropathic pain.

Functional mitral stenosis after mitral valve repair for Type II dysfunction: determinants and impacts on long-term outcome.[Pubmed:29490023]

Eur J Cardiothorac Surg. 2018 Sep 1;54(3):453-459.

OBJECTIVES: This study was performed to analyse the impacts of functional mitral stenosis (MS) following mitral valve (MV) repair on late cardiac function and new onset of atrial fibrillation or survival. METHODS: We retrospectively reviewed 602 patients with mitral regurgitation who underwent MV repair for Type II dysfunction from 2001. Functional MS was diagnosed when the mean transmitral pressure gradient (MTPG) was >/=5 mmHg on postoperative echocardiography. We analysed preoperative and surgical risk factors for functional MS (MS group). We then compared long-term outcomes and late cardiac function over time between patients in the MS and no-MS groups using a mixed-effects model with repeated measures. RESULTS: On postoperative echocardiography, 51 patients had an MTPG of >/=5 mmHg (MS group) and 551 had an MTPG of <5 mmHg (no-MS group). Only the ring size was an independent predictor of MS (28.8 +/- 2.1 mm in the no-MS group vs 28.0 +/- 1.9 mm in the MS group, P = 0.004). During follow-up, increases in the tricuspid regurgitation (TR) pressure gradient (PRV-RA) and TR severity over time were significantly greater in the MS group than in the no-MS group (PRV-RA: 0.72 +/- 0.16 vs 0.35 +/- 0.17 mmHg per year, respectively, P = 0.03; TR severity: 0.072 +/- 0.014 vs 0.034 +/- 0.015 per year, respectively, P = 0.0113). Moreover, the 10-year rate of new onset of atrial fibrillation was significantly lower in the MS group than in the no-MS group (37.5% vs 16.9%, respectively; log-rank P = 0.003). CONCLUSIONS: Annuloplasty using a small-sized ring in MV repair caused a postoperative high MTPG, which induced an elevation in the pulmonary artery pressure and residual TR grade and causing new onset of atrial fibrillation despite a competent MV.

Impact of Mean Transaortic Pressure Gradient on Long-Term Outcome in Patients With Severe Aortic Stenosis and Preserved Left Ventricular Ejection Fraction.[Pubmed:28572283]

J Am Heart Assoc. 2017 Jun 1;6(6). pii: JAHA.117.005850.

BACKGROUND: Mean transaortic pressure gradient (MTPG) has never been validated as a predictor of mortality in patients with severe aortic stenosis. We sought to determine the value of MTPG to predict mortality in a large prospective cohort of severe aortic stenosis patients with preserved left ventricular ejection fraction and to investigate the cutoff of 60 mm Hg, proposed in American guidelines. METHODS AND RESULTS: A total of 1143 patients with severe aortic stenosis defined by aortic valve area MTPG >/=40 mm Hg were included. The population was divided into 3 groups according to MTPG: between 40 and 49 mm Hg, between 50 and 59 mm Hg, and >/=60 mm Hg. The end point was all-cause mortality. MTPG was >/=60 mm Hg in 392 patients. Patients with MTPG >/=60 mm Hg had a significantly increase risk of mortality compared with patients with MTPG <60 mm Hg (hazard ratio [HR]=1.62 [1.27-2.05] P<0.001), even for the subgroup of asymptomatic or minimally symptomatic patients (HR=1.56 [1.04-2.34] P=0.032). After adjustment for established outcome predictors, patients with MTPG >/=60 mm Hg had a significantly higher risk of mortality than patients with MTPG <60 mm Hg (HR=1.71 [1.33-2.20] P<0.001), even after adjusting for surgery as a time-dependent variable (HR=1.71 [1.43-2.11] P<0.001). Similar results were observed for the subgroup of asymptomatic or minimally symptomatic patients (HR=1.70 [1.10-2.32] P=0.018 and HR=1.68 [1.20-2.36] P=0.003, respectively). CONCLUSIONS: This study shows the negative prognostic impact of high MTPG (>/=60 mm Hg), on long-term outcome of patients with severe aortic stenosis with preserved left ventricular ejection fraction, irrespective of symptoms.

Subprosthetic Pannus after Aortic Valve Replacement Surgery: Cardiac CT Findings and Clinical Features.[Pubmed:25902187]

Radiology. 2015 Sep;276(3):724-31.

PURPOSE: To investigate the cardiac computed tomographic (CT) findings and clinical implications of subprosthetic pannus in patients who have undergone aortic valve replacement. MATERIALS AND METHODS: The institutional review board approved this retrospective study, and the need to obtain written informed consent was waived. From April 2011 to March 2012, 88 patients (mean age, 63 years; 45 men) with a prosthetic aortic valve who underwent cardiac CT were retrospectively selected. Dynamic cardiac CT images were analyzed by using a multiplanar reformatted technique. The presence or absence of subprosthetic pannus and its extent were evaluated at cardiac CT. The geometric orifice area and the effective orifice area of each prosthetic valve were measured to enable analysis of the pannus encroachment ratio in the systolic phase. Hemodynamic parameters at echocardiography, including mean transprosthetic pressure gradient (MTPG), were compared between patients with and those without pannus. The encroachment ratio and the MTPG were correlated by using the Spearman test to evaluate the relationship between the two variables. RESULTS: Seventeen patients (19%) had subprosthetic pannus at cardiac CT. In patients with subprosthetic pannus, MTPG, peak pressure gradient, transvalvular peak velocity, and left ventricular ejection fraction (LVEF) were significantly higher than in patients without pannus (MTPG: 28.1 mm Hg +/- 19.8 [standard deviation] vs 14.0 mm Hg +/- 6.5, P = .004; peak pressure gradient: 53.1 mm Hg +/- 38.4 vs 26.1 mm Hg +/- 11.4, P = .004; transvalvular peak velocity: 3.3 m/sec +/- 1.3 vs 2.5 m/sec +/- 0.5; and LVEF: 64.7% +/- 7.4 vs 56.8% +/- 10.5, P = .004). A high MTPG (>/=40 mm Hg) was observed in four patients at echocardiography, and subprosthetic panni were identified at CT in all four patients. In patients with increased MTPGs, the encroachment ratio by subprosthetic pannus at CT was significantly higher than that in patients with MTPGs of less than 40 mm Hg (42.7 +/- 13.3 vs 7.6 +/- 3, P = .012). CONCLUSION: Cardiac CT revealed subprosthetic pannus to be a cause of the hemodynamic changes in patients who had undergone aortic valve replacement. By helping quantify the encroachment ratio by pannus, cardiac CT may help differentiate which subprosthetic panni might lead to substantial flow limitation over the prosthetic aortic valve.

[Clinical value of NT-proBNP in the diagnosis and analysis of correlation of NT-proBNP with clinical and echocardiographic findings in patients with aortic stenosis].[Pubmed:21029666]

Zhonghua Yi Xue Za Zhi. 2010 Aug 24;90(32):2233-6.

OBJECTIVE: To evaluate the diagnostic value of NT-proBNP in patients with aortic stenosis (AS), analyze the relation of NT-proBNP to NYHA functional class and echocardiographic findings. METHODS: Measured the whole venous blood of NT-proBNP with enzyme linked immuno sorbent assay in 40 aortic stenosis patients (AS group) and 76 normal subjects (control group). We assessed the diagnostic value of NT-proBNP for aortic stenosis, and related NT-proBNP to clinical NYHA functional class and echocardiographic findings. RESULTS: Compared to controls, NT-proBNP levels had significantly higher in patients with aortic stenosis (P < 0.01). The level of NT-proBNP was gradually and significantly increased with the NYHA functional II, III and IV class compared to controls (all P < 0.01). NT-proBNP was significantly (3.5 times) higher in mild/moderate stenosis group than that in control group (2.95 +/- 0.48 vs 2.63 +/- 0.10, P < 0.05), and was significantly (6.0 times) higher in severe stenosis group than that in control group (3.16 +/- 0.50 vs 2.63 +/- 0.10, P < 0.01). LVMI was significantly (1.7 times) higher in mild/moderate stenosis group than that in control group (169 +/- 51 vs 100 +/- 22, P < 0.01), and was significantly (2.1 times) higher in severe stenosis group than that in control group (212 +/- 86 vs 100 +/- 22, P < 0.01). The NT-proBNP values of 1150 ng/L and 1356 ng/L were determined as the best cutoff values for the diagnosis of patients with mild/moderate (AUC = 0.657, P < 0.05) and severe aortic stenosis (AUC = 0.848, P < 0.01), the sensitivity, specificity and accuracy were 61.11% and 77.30%, 69.74% and 96.10%, 68.09% and 91.80%. Log (NT-proBNP) was significantly positively related with LVEDD, LVMI and mean transvalvular pressure gradient (MTPG) (all P < 0.05), and negatively related with LVEF (P = 0.01) in univariate analysis. In multiple regression analyses, NYHA functional class, LVEF and Log (MTPG) was independently associated with NT-proBNP. CONCLUSION: NT-proBNP is valuable for the diagnosis of patients with aortic stenosis. NT-proBNP has correlation with the heart function and severity of the aortic stenosis.

[The role of NO resulted from neuronal nitric oxide synthase in the metabotropic glutamate receptor2/3 mediated-brain ischemic tolerance].[Pubmed:21189546]

Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2009 May;25(2):182-5.

AIM: To explore the role of nitric oxide (NO) resulted from nNOS in the mGluR2/3 mediated-brain ischemic tolerance induced by cerebral ischemic preconditioning (CIP), the present study is undertaken to observe the influences of alpha-methyl-(4-tetrazolyl-phenyl) glycine (MTPG), an antagonist of mGluR2/3, on the expression of nNOS during the induction of the brain ischemic tolerance based on confirming the blocking effect of MTPG on the induction of the tolerance. METHODS: Thirty-six Sprague-Dawley rats, whose vertebral arteries were permanently occluded, were randomly divided into sham, CIP, ischemic insult, CIP+ ischemic insult, MTPG+ CIP and MTPG+ CIP+ ischemic insult groups. Thionin staining and immunohistochemistry were used for neuropathological evaluation and assay of nNOS expression in the hippocampal CA1 subregion of the rats. RESULTS: The expression of nNOS showed moderate and extreme up-regulation in the CIP and ischemia groups, respectively, compared to the sham group. The preceded CIP blocked in certain extent the extreme up-regulation of nNOS induced by brain ischemia in CIP + ischemia group. Administration of MTPG via lateral cerebral ventricle 20 min before CIP blocked the up-regulation of nNOS induced by CIP, but had no influence on the pyramidal neuronal survival. While in the MTPG+ CIP+ ischemic insult group, the expression of nNOS was stronger than that in the MTPG + CIP group, and the up-regulation was accompanied with obvious delayed neuronal death. Discussion concerned illustrated that the relative intensive up-regulation of nNOS in this group might be attributed to brain ischemia other than MTPG. CONCLUSION: NO resulted from nNOS participated the induction of mGluR2/3 mediated-brain ischemic tolerance as a downstream molecule of activation of mGluR2/3 during CIP.

Edge-to-edge repair for mitral regurgitation: a clinical and exercise echocardiographic study.[Pubmed:18980081]

J Heart Valve Dis. 2008 Sep;17(5):476-84.

BACKGROUND AND AIM OF THE STUDY: The durability and potential for creating functional mitral stenoses are major concerns in the edge-to-edge (E-to-E) repair of mitral regurgitation (MR). METHODS: Valve repair for MR was performed using the classical Carpentier technique in 120 patients (group C), and with the E-to-E technique in 37 patients (group E). A ring annuloplasty was performed in all patients. The mid-term results were examined and exercise echocardiography was conducted. RESULTS: No significant differences were observed between the two groups with regards to early and late mortality rates, actuarial survival rate and valve-related complication-free rate at five years after surgery. Postoperatively, MR was decreased significantly in both groups. Exercise echocardiography was undertaken in 35 operative survivors (20 from group C, 15 from group E). At peak exercise, the mean transmitral pressure gradient (MTPG) increased significantly in both groups. Systolic pulmonary artery pressure (SPAP) was also significantly elevated, but still within the accepted upper limits in both groups. The mitral valve area (MVA) showed no significant increase in either group. At peak exercise there were no significant differences in MTPG, SPAP and MVA between the two groups. CONCLUSION: Edge-to-edge repair is equally effective and durable as a conventional repair using the Carpentier technique. A mitral valve redesigned by E-to-E repair with ring annuloplasty may be slightly restrictive compared to a normal healthy mitral valve under exercise conditions; however, the hemodynamic performance did not differ significantly from that of a valve repaired with the Carpentier technique. These hemodynamics were not related to the use of E-to-E repair per se as the only causal factor, but rather to the ring annuloplasty.

Interleukin-18 mediated inhibition of LTP in the rat dentate gyrus is attenuated in the presence of mGluR antagonists.[Pubmed:17123727]

Neurosci Lett. 2007 Feb 2;412(3):206-10.

Pro-inflammatory cytokines are known to be elevated in several neuropathological states that are associated with learning and memory impairments. We have previously demonstrated the inhibition of long-term potentiation (LTP), a recognised model for memory, in the dentate gyrus region of the rat hippocampus, by interleukin-18. We have also previously shown that the inhibitory effect of TNF-alpha on LTP can be attenuated by inhibitors of metabotropic glutamate receptors (mGluRs). We therefore went on to investigate the effects of the mGluR antagonists MPEP and MTPG on the effect of IL-18 on LTP in the rat dentate gyrus in vitro. Recordings of field excitatory post-synaptic potentials (EPSPs) were made from the medial perforant path of rat hippocampal slices. IL-18 (100 ng/ml) applied for 20 min before-HFS had no significant effect on baseline EPSPs but significantly impaired LTP (IL-18 LTP 116+/-9%, versus control LTP 163+/-6% 1h post-tetanus, P<0.001, n=5). Perfusion of the mGluR5 specific antagonist MPEP (5 microM) for 40 min prior to application of IL-18 had no significant effect on baseline EPSPs but significantly attenuated the inhibitory effect of IL-18 on LTP at 30 min but not 1h (177+/-2% and 138+/-8%, respectively, compared to controls; n=5). Perfusion of the group II mGluR antagonist MTPG (50 microM) for 40 min prior to application of IL-18 had no significant effect on baseline EPSPs but was found to significantly reverse the inhibitory effect of IL-18 on LTP at 1h (164+/-6% compared to IL-18 alone, n=5). This study provides novel evidence of the involvement of mGluRs in the IL-18 mediated inhibition of LTP.

Group II metabotropic glutamate receptor-mediated regulation of dopamine release from slices of rat nucleus accumbens.[Pubmed:16781059]

Neurosci Lett. 2006 Aug 14;404(1-2):182-6.

The role of metabotropic glutamate receptors (mGluRs) in the regulation of dopamine release in the rat nucleus accumbens was investigated. Fifteen millimolar of KCl stimulated the release of [(3)H]dopamine from the slices of the rat nucleus accumbens. Both an mGluR agonist 1S,3R-1-amino-cyclopentane-1,3-dicarboxylate (ACPD) and a preferential group II mGluR agonist, (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-1), significantly inhibited the KCl-evoked [(3)H]dopamine release in the nucleus accumbens. This inhibitory effect of L-CCG-1 on the KCl-evoked dopamine release was significantly attenuated by preferential group II mGluR antagonists such as (2S,3S,4S)-2-methyl-2-(carboxypropyl)glycine (MCCG) and (RS)-alpha-methyl-4-tetrazolylphenylglycine (MTPG); in contrast, the preferential group III mGluR agonist L-2-amino-4-phosphonobutylate (L-AP4), failed to show any effect on the KCl-evoked [(3)H]dopamine release in the nucleus accumbens. Moreover, the inhibitory effect of L-CCG-1 on the KCl-evoked [(3)H]dopamine release from the slices of the rat nucleus accumbens was preserved in the presence of tetrodotoxin. These results show that group II mGluRs may play a more significant role in regulating dopamine release than group III mGluRs, and that the group II mGluRs may negatively regulate dopamine release, presumably through those expressed at the dopaminergic nerve terminals or through those expressed at glutamatergic nerve terminals in the nucleus accumbens.

NMDA and group I metabotropic glutamate receptors activation modulates substance P release from the arcuate nucleus and median eminence.[Pubmed:16226374]

Neurosci Lett. 2006 Jan 23;393(1):60-4.

Glutamate participates in the regulation of secretion of several neuropeptides, including substance P (SP). Glutamate acts through ionotropic (iGluR) and metabotropic (mGluR) receptors. We have investigated whether glutamate receptor agonists and antagonists could affect SP release from the arcuate nucleus and the median eminence (ARC/ME). An increase in SP-like immunoreactivity (SP-LI) release from ARC/ME was induced by glutamate and N-methyl-D-aspartate (NMDA). This increase was prevented by D-(-)-2-amino-5-phosphono pentanoic acid (DAP5) (0.1mM), a specific NMDA antagonist and by (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA) (0.1 mM), a selective antagonist of group I mGluR. The selective non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3(1H-4H)-dione (DNQX) (0.1mM) and (RS)-alpha-methyl-4-tetrazolylphenylglycine (MTPG) (0.1 mM), a group II and III mGluRs antagonist, did not affect the stimulatory effect of glutamate. A group I selective agonist, (S)-3,5-dihydroxyphenylglycine (DHPG) induced a significant increase in SP-LI release. Supporting the participation of nitric oxide (NO) in the effect of glutamate on SP-LI release, NAME (0.5 mM), a NO synthase inhibitor, reduced the glutamate-induced increase in SP-LI release from ARC/ME. Similarly, glutamate did not induce an increase in SP-LI release in the presence of meloxicam (0.1 mM) (a cyclooxygenase-2 (COX-2) specific inhibitor) indicating that prostaglandins production may also be involved in the glutamate effect. These data indicate that glutamate increases SP-LI release from the ARC/ME by acting through NMDA and group I mGluRs in the male rat. This stimulatory effect could be mediated by nitric oxide and prostaglandin production.

[Effects of alpha-methyl-(4-tetrazolyl-phenyl) glycine on the induction of hippocampal ischemic tolerance in the rat].[Pubmed:12817298]

Sheng Li Xue Bao. 2003 Jun 25;55(3):303-10.

To explore the role of metabotropic glutamate receptor 2/3 mGluR 2/3 in the induction of brain ischemic tolerance (BIT), the influences of mGluR2/3 antagonist alpha-methyl-(4-tetrazolyl-phenyl) glycine (MTPG) on the induction of BIT and expression of glial fibrillary acidic protein (GFAP) in the hippocampus were observed using thionin staining and GFAP immunohistochemical staining in a rat brain ischemic model with four-vessel occlusion (4VO). Fifty-four rats, of which bilateral vertebral arteries were occluded permanently by electrocautery, were divided into 5 groups: (1) sham operated group (n=8): the bilateral carotid common arteries (BCCA) were separated, but the blood flow was not blocked; (2) ischemia group (n=8): the blood flow of BCCA was blocked for 8 min; (3) ischemic preconditioning (IP) group (n=8): the blood flow of BCCA was occluded for 3 min as a cerebral ischemic preconditioning (CIP), and then the rats were exposed to an 8-min brain ischemic insult 24 h after the CIP; (4) MTPG+IP group (n=22): MTPG was administered 20 min before the CIP, then the rats were exposed to an 8-min brain ischemia insult 24 h after the CIP. In order to examine dosage dependency in the effect of MTPG, 4 dosages of MTPG (0.4, 0.2, 0.04 and 0.008 mg) were administered; (5) MTPG+ischemia group (n=8): an ischemic insult for 8 min was given 24 h after the administration of MTPG (0.2 mg). MTPG was injected into the right lateral cerebral ventricle. The results obtained are as follows. (1) Ischemic insult for 8 min increased the histological grade (HG) and reduced the neuronal density (ND) significantly, and also increased the expression of GFAP significantly (P<0.05 vs sham-operated group). (2) In the IP group, the above changes were not observed, indicating that CIP could protect pyramidal neurons against the ischemic insult. (3) The protective effects of CIP were blocked by MTPG, as manifested by the significant increase in HG and decrease in ND in the MTPG+IP group (P<0.05 vs sham-operated group). The changes were dose-dependent. (4) No obvious difference in the HG, ND and expression of GFAP was detected between the groups of MTPG+ischemia and ischemia. The above results indicate that MTPG blocks the induction of BIT induced by CIP, suggesting that mGluR2/3 participates in the induction of BIT.

Novel potent selective phenylglycine antagonists of metabotropic glutamate receptors.[Pubmed:8864696]

Eur J Pharmacol. 1996 Aug 1;309(1):71-8.

The metabotropic glutamate (mGlu) receptor antagonist properties of novel phenylglycine analogues were investigated in adult rat cortical slices (mGlu receptors negatively coupled to adenylyl cyclase), neonatal rat cortical slices and in cultured rat cerebellar granule cells (mGlu receptors coupled to phosphoinositide hydrolysis). (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG), (RS)-alpha-methyl-4-sulphonophenylglycine (MSPG), (RS)-alpha-methyl-4-tetrazolylphenylglycine (MTPG), (RS)-alpha-methyl-3-carboxymethyl-4-hydroxyphenylglycine (M3CM4HPG) and (RS)-alpha-methyl-4-hydroxy-3-phosphonomethylphenylglycine (M4H3PMPG) were demonstrated to have potent and selective effects against 10 microM L-2-amino-4-phosphonobutyrate (L-AP4)- and 0.3 microM (2S,1'S,2'S)-2-(2-carboxycyclopropyl)glycine (L-CCG-1)-mediated inhibition of forskolin-stimulated cAMP accumulation in the adult rat cortex. In contrast, these compounds demonstrated either weak or no antagonism at mGlu receptors coupled to phosphoinositide hydrolysis in either neonatal rat cortex or in cultured cerebellar granule cells. These compounds thus appear to be useful discriminatory pharmacological tools for mGlu receptors and form the basis for the further development of novel antagonists.

Pharmacological antagonism of the actions of group II and III mGluR agonists in the lateral perforant path of rat hippocampal slices.[Pubmed:8730739]

Br J Pharmacol. 1996 Apr;117(7):1457-62.

1. An understanding of the physiological and pathological roles of metabotropic glutamate receptors (mGluRs) is currently hampered by the lack of selective antagonists. Standard extracellular recording techniques were used to investigate the activity of recently reported mGluR antagonists on agonist-induced depressions of synaptic transmission in the lateral perforant path of hippocampal slices obtained from 12-16 day-old rats. 2. The group III specific mGluR agonist, (S)-2-amino-4-phosphonobutanoate (L-AP4) depressed basal synaptic transmission in a reversible and dose-dependent manner. The mean (+/-s.e. mean) depression obtained with 100 microM L-AP4 (the maximum concentration tested) was 74 +/- 3% and the IC50 value was 3 +/- 1 microM (n = 5). 3. The selective group II mGluR agonists, (1S,3S)-1-aminocyclopentane-1, 3-dicarboxylate ((1S,3s)-ACPD) and (2S, 1'R, 2'R, 3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) also depressed basal synaptic transmission in a reversible and dose-dependent manner. The mean depression obtained with 200 microM (1S,3S)-ACPD was 83 +/- 8% and the IC50 value was 12 +/- 3 microM (n = 5). The mean depression obtained with 1 microM DCG-IV was 73 +/- 7% and the IC50 value was 88 +/- 15 nM (n = 4). 4. Synaptic depressions induced by the actions of 20 microM (1S,3S)-ACPD and 10 microM L-AP4 were antagonized by the mGluR antagonists (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG), (S)-2-methyl-2-amino-4-phosphonobutanoate (MAP4), (2S,1'S,2'S)-2-methyl-2(2'-carboxycyclopropyl)glycine (MCCG), (RS)-alpha-methyl-4-tetrazolylphenylglycine (MTPG), (RS)-alpha-methyl-4-sulphonophenylglycine (MSPG) and (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG) (all tested at 500 microM). 5. (+)-MCPG was a weak antagonist of both L-AP4 and (1S,3S)-ACPD-induced depressions. MCCG was selective towards (1S,3S)-ACPD, but analysis of its effects were complicated by apparent partial agonist activity. MAP4 showed good selectivity for L-AP4-induced effects. 6. The most effective antagonist tested against 10 microM L-AP4 was MPPG (mean reversal 90 +/- 3%; n = 4). In contrast, the most effective antagonist tested against 20 microM (1S,3S)-ACPD induced depressions was MTPG (mean reversal 64 +/- 4%; n = 4). Both antagonists produced parallel shifts in agonist dose-response curves. Schild analysis yielded estimated KD values of 11.7 microM and 27.5 microM, respectively. Neither antagonist had any effect on basal transmission or on depressions induced by the adenosine receptor agonist, 2-chloroadenosine (500 nM; n = 3). 7. We conclude that both group II and group III mGluRs can mediate synaptic depressions induced by mGluR agonists in the lateral perforant path. The mGlur antagonists MTPG, MPPG and MAP4 should be useful in determining the roles of group II and III mGluRs in the central nervous system.

New phenylglycine derivatives with potent and selective antagonist activity at presynaptic glutamate receptors in neonatal rat spinal cord.[Pubmed:8532166]

Neuropharmacology. 1995 Aug;34(8):851-6.

The depression of the monosynaptic excitation of neonatal rat motoneurones produced by the metabotropic glutamate receptor (mGluR) agonists (1S,3S)-1-aminocyclopentane-1, 3-dicarboxylate (ACPD) or L-2-amino-4-phosphonobutyrate (L-AP4) was antagonized by three novel phenylglycine analogues: (RS)-alpha-methyl-4-sulphonophenylglycine (MSPG), (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG) and (RS)-alpha-methyl-4-tetrazolylphenylglycine (MTPG). The potencies of all the new compounds were greater than that of the previously reported (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG). For L-AP4-sensitive presynaptic mGluRs, the order of antagonist potency found was MPPG > MSPG > MTPG > MCPG. In contrast, the order of antagonist potency found for (1S,3S)-ACPD-sensitive presynaptic mGluRs was MTPG > MPPG > MSPG > MCPG. To date, MPPG (KD 9.2 microM) is the most potent L-AP4-sensitive receptor antagonist yet tested on the neonatal rat spinal cord. In addition, MTPG (KD 77 microM) is the most potent antagonist yet tested for (1S,3S)-ACPD-sensitive receptors in this preparation.