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Biomedical subjects

L Singh

Publications and source records attributed to L Singh.

At least 127 records · Page 7Linked to original sources
PubMed1990

Enantiomers of HA-966 (3-amino-1-hydroxypyrrolid-2-one) exhibit distinct central nervous system effects: (+)-HA-966 is a selective glycine/N-methyl-D-aspartate receptor antagonist, but (-)-HA-966 is a potent gamma-butyrolactone-like sedative.

The antagonist effect of (+/-)-3-amino-1-hydroxypyrrolid-2-one (HA-966) at the N-methyl-D-aspartate (NMDA) receptor occurs through a selective interaction with the glycine modulatory site within the receptor complex. When the enantiomers of (+/-)-HA-966 were resolved, the (R)-(+)-enantiomer was found to be a selective glycine/NMDA receptor antagonist, a property that accounts for its anticonvulsant activity in vivo. In contrast, the (S)-(-)-enantiomer was only weakly active as an NMDA-receptor antagonist, but nevertheless it possessed a marked sedative and muscle relaxant action in vivo. In radioligand binding experiments, (+)-HA-966 inhibited strychnine-insensitive [3H]glycine binding to rat cerebral cortex synaptic membranes with an IC50 of 12.5 microM, whereas (-)-HA-966 had an IC50 value of 339 microM. In electrophysiological experiments, (+)-HA-966 selectively antagonized NMDA receptor responses in rat cortical slices, whereas the (-)-enantiomer was much weaker. On cultured cortical neurones (+)-HA-966 inhibited glycine-potentiated NMDA responses with an IC50 = 13 microM compared with (-)-HA-966, which has an IC50 = 708 microM. In agreement with findings with racemic HA-966, even high concentrations of (+)-HA-966 did not completely inhibit NMDA responses, suggesting that (+)-HA-966 is a low-efficacy partial agonist. (+)-HA-966 produced parallel shifts to the right of the glycine concentration curve for potentiation of NMDA responses, resulting in an estimated pKb = 5.6. In mice, (+)-HA-966 antagonized sound and N-methyl-DL-aspartic acid (NMDLA)-induced seizures with ED50 values of 52.6 mg/kg of body weight (i.p.) and 900 mg/kg (i.v.), respectively. The coadministration of D-serine dose-dependently (10-100 micrograms into the cerebral ventricles per mouse) antagonized the anticonvulsant effect of a submaximal dose of (+)-HA-966 (100 micrograms administered directly into the cerebral ventricles) against NMDLA-induced seizures. The sedative/ataxic effect of racemic HA-966 was mainly attributable to the (-)-enantiomer, which was greater than 25-fold more potent than the (+)-enantiomer. It is suggested that, as in the case of the sedative gamma-butyrolactone, disruption of striatal dopaminergic mechanisms may be responsible for this action.

4-Butyrolactone↗
PubMed1990

The pharmacological properties of the imidazobenzodiazepine, FG 8205, a novel partial agonist at the benzodiazepine receptor.

1. The pharmacological properties of the benzodiazepine receptor ligand, FG 8205 (7-chloro-5,6-dihydro-5-methyl-6-oxo-3-(5-isopropyl-1,2,4-oxadiazol++ +-3-yl)-4H- imidazol[1,5a][1,4]benzodiazepine) have been examined. 2. FG 8205 potently displaced [3H]-flumazenil binding in rat cortical membranes with a Ki of 3.3 nM, but was inactive at 13 neurotransmitter recognition sites. 3. Consistent with a partial agonist profile, the affinity of FG 8205 for the benzodiazepine recognition site was increased in the presence of gamma-aminobutyric acid (GABA, 300 microM) by a degree (-log [IC50 in the presence of GABA/IC50 alone] = 0.34) significantly less than found for diazepam (0.46). FG 8205 also potentiated the inhibitory potency of the GABAA-receptor agonist, isoguvacine, on the hippocampal CA1 population spike and, again, the maximum shift (-log dose-ratio = 0.2) was significantly less than that seen with diazepam (0.4). 4. In anticonvulsant studies, the ED50 doses of FG 8205 and diazepam needed to antagonize seizures induced by pentylenetetrazol (PTZ) or by sound in audiogenic seizure prone mice were similar with values of 0.2-0.3 mg kg-1, i.p. However, even high doses of FG 8205 (50 mg kg-1) did not protect against seizures induced by electroshock. 5. FG 8205 released responding suppressed by footshock in a rat operant conditioned emotional response task over the dose range 0.5-50 mg kg-1 (i.p.). Similar doses of FG 8205 had a marked taming effect in cynomolgus monkeys. However, measures of sedation and ataxia (as measured by rotarod in the mouse, climbing behaviour in the rat, and by scoring arousal and co-ordination in primates) were slight and only transiently affected by FG 8205, and FG 8205 significantly antagonized the rotarod performance deficit induced by diazepam in the mouse. 6. While the potentiation by FG 8205 of the response to isoguvacine in the rat hippocampal slice and the anxiolytic-like effects of the compound in both rats and primates were reversed by the benzodiazepine receptor antagonist, flumazenil, high doses of the antagonist were able only marginally to block the protective effects of FG 8205 against seizures induced by PTZ in the mouse. 7. Thus, FG 8205 does not show the marked motor impairment characteristic of full agonists at the benzodiazepine receptor, consistent with its partial agonist profile in in vitro assay systems. Nevertheless, the compound has sufficient intrinsic activity to maintain high efficacy in anticonvulsant and anxiolytic tests.

Animals↗
PubMed1990

Evidence against an involvement of the haloperidol-sensitive sigma recognition site in the discriminative stimulus properties of (+)-N-allylnormetazocine ((+)-SKF 10,047).

1. The involvement of the haloperidol-sensitive, sigma recognition site and the N-methyl-D-aspartic acid (NMDA) receptor in the mediation of the discriminative stimulus properties of (+)-N-allylnormetazocine [+)-NANM, (+)-SKF 10,047), has been investigated in the rat by use of a two-lever, operant drug discrimination paradigm. 2. Six compounds with nanamolar affinity for the sigma recognition site [+/-)-pentazocine, (+)-3-(hydroxyphenyl)-N-propylpiperidine [+)-3-PPP), ditolylguanidine (DTG), haloperidol, (-)-butaclamol and BMY 14802) were investigated for their ability to generalise or antagonise the (+)-NANM discriminative stimulus. Each drug was tested at doses found in an ex vivo radioligand binding assay to displace [3H]-DTG from the central sigma recognition site by more than 40%. 3. While (+/-)-pentazocine (in the presence of naloxone) generalised and (+)-3-PPP partially antagonised the (+)-NANM cue, the other putative sigma ligands were ineffective either as agonists or antagonists at doses clearly occupying the sigma site in vivo. 4. Dose-dependent generalisation to the (+)-NANM cue was seen with the selective non-competitive NMDA receptor antagonist, MK-801, a compound devoid of significant affinity for the sigma recognition site. 5. (+/-)-Pentazocine was found to antagonise seizures induced in the mouse by NMDLA, a model reflecting antagonism of central NMDA receptors, and a strong correlation was found between the rank order of potency of compounds to generalise to the (+)-NANM discriminative stimulus and their potencies as anticonvulsants. 6. In conclusion, no evidence was found to substantiate the contention that the discriminative stimulus properties of (+)-NANM are mediated by the haloperidol-sensitive sigma recognition site. On the other hand, the results are consistent with the interoceptive stimulus being mechanistically based in the NMDA receptor complex.

Animals↗
PubMed1990

Modulation of seizure susceptibility in the mouse by the strychnine-insensitive glycine recognition site of the NMDA receptor/ion channel complex.

1. In order to determine whether the strychnine-insensitive glycine modulatory site on the N-methyl-D-aspartate (NMDA) receptor/ion channel complex is fully activated in vivo, the ability of the selective glycine receptor agonist, D-serine, to modulate seizure susceptibility in the mouse has been examined. 2. D-Serine (10-200 micrograms per mouse, i.c.v.) dose-dependently increased the potency of NMDLA in inducing seizures in Swiss Webster mice by approximately 3 fold. L-Serine was without significant effect. 3. The potency of pentylenetetrazol in inducing seizures was also enhanced by D-, but not L-serine, although the magnitude of the shift (1.6 fold) was considerably less than for NMDLA. 4. Similar doses of D-serine were also able to block the anticonvulsant effect of the non-selective glycine receptor antagonist, kynurenic acid, against seizures induced by NMDLA, but were without effect on the anticonvulsant effect of the competitive NMDA receptor antagonist, 3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). 5. D-Serine completely antagonized the protective effect of the selective glycine receptor antagonist, 7-chlorokynurenic acid, against sound-induced seizures in DBA/2 mice, but was less effective in this model against the less selective antagonist, kynurenic acid. 6 The results indicate that in vivo, NMDA receptors are not maximally potentiated by endogenous glycine and suggest an important involvement of the glycine modulatory site on the NMDA receptor/ion channel complex in the pathophysiology of epilepsy.

Acoustic Stimulation↗
PubMed1989

The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor.

The selective non-competitive NMDA receptor antagonist, MK-801, potently blocked convulsions induced in the mouse by N-methyl-DL-aspartic acid (NMDLA) with an i.v. ED50 dose of 0.2 mg/kg. Similar doses of MK-801 were also effective in blocking seizures induced by pentylenetetrazol (PTZ), electroshock and by sound in audiogenic seizure-prone animals. Other less selective non-competitive NMDA receptor antagonists including phencyclidine (PCP), thienylcyclohexylpiperidine (TCP), (+)-N-allylnormetazocine [+)-NANM, (+)-SKF 10,047) and ketamine also blocked NMDLA-induced seizures with a rank order of potency of MK-801 greater than PCP greater than TCP = (+)-NANM greater than ketamine. The competitive NMDA receptor antagonist, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) blocked NMDLA-induced seizures with an ED50 of 4.5 mg/kg, 22- and 560-fold more potently than the competitive antagonists, 2-DL-amino-7-phosphonoheptanoic acid (2-APH) and 2-DL-amino-5-phosphonovaleric acid (2-APV), respectively. MK-801 was the most potent of the non-competitive antagonists to induce a motor syndrome including head weaving, body rolling, increased locomotion and ataxia, characteristic of the behavioural response to PCP in the mouse. The syndrome was also present following injection of the competitive NMDA receptor antagonists, although they were generally less potent (probably a reflection of poor brain penetration) and less efficacious than the non-competitive antagonists. For all compounds except CPP, the anticonvulsant ED50 dose was close to the minimum effective dose to induce motor stimulation: CPP was 5- to 10-fold more potent as an anticonvulsant.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Breast cancer, prostaglandins and patient survival.

Prostaglandins may have both undesirable and desirable effects in malignant disease. Their possible roles in breast cancer were studied by examining the relationships between different variables and the amounts of prostaglandin-like material (PG-LM) extracted from 141 breast carcinomas. Univariate analysis indicates a direct correlation with patient age and menopausal status, with a greater yield from cancers of post- compared with pre-menopausal women. Tumours up to 2 cm diameter yielded more PG-LM than those measuring greater than 2-5 cm. Although there was also a direct correlation with bone metastasis near to the time of surgery, this was because no positive bone scans occurred in patients whose tumours yielded little total PG-LM (less than 16 ng PGE2 equivalents per g tissue). Since tumour PG-LM did not predict later spread to bone, and yields of greater than 16 ng g-1 were similar in the positive and negative bone scan groups, tumour PG-LM appears to be unimportant for skeletal metastasis. There was no obvious relationship of tumour PG-LM to the grade of malignancy, tumour type, amounts of fibrous tissue (and therefore malignant cells), invasion of blood vessels and lymphatics or presence of plasma cells. Multivariate analysis indicates that disease-free survival is longest with an intermediate production of tumour total PG-LM. Of the 82 patients now dead, the cause was attributed to metastatic disease in 69 cases. No relationship of PG-LM to the length of survival was seen with univariate or multivariate analysis. However, when just the post-menopausal patients who died within the first 3 postoperative years were analysed, there was a highly significant inverse correlation between the tumour total PG-LM and the time to death. The reason(s) for these different findings on overall survival compared with just the patients who died are not understood, but the results may indicate that one or more other variables must co-exist with a high tumour PG-LM to hasten death.

Bone Neoplasms↗
PubMed1989

Trace elements in the endometrium of infertile women.

Some essential trace elements were estimated in endometrium of regularly menstruating fertile women and in women with infertility due to cervical factors. The distribution of the trace elements zinc, copper, iron, selenium and manganese at any particular phase of cycle remains more or less semilier between control (i.e. fertile) and infertile (primary and secondary) subjects.

Adult↗
PubMed1988

In vivo labelling of the NMDA receptor channel complex by [3H]MK-801.

An in vivo radioligand binding assay for the N-methyl-D-aspartate (NMDA) receptor channel complex in the mouse brain has been developed using the non-competitive NMDA receptor antagonist [3H]MK-801. In vivo binding of [3H]MK-801 was displaced by MK-801 (ED50 = 0.17 mg/kg i.p.), (-)-MK-801 (1.0 mg/kg), thienylcyclohexylpiperidine (1.8 mg/kg), etoxadrol (5.1 mg/kg) and (+)-SKF 10,047 (34.5 mg/kg). The potency of these drugs in this in vivo binding assay was highly correlated (r = 0.97) with their functional effects as antagonists of N-methyl-DL-aspartate-induced tonic convulsions.

Affinity Labels↗
PubMed1988

Restriction fragment polymorphism in the sex-determining region of the Y chromosomal DNA of European wild mice.

Using 32P-labeled probe consisting mainly of (GATA)n we have shown that a male specific Alu1 DNA blot pattern which defines the Y chromosome sex-determining locus in inbred mice is highly polymorphic in wild mice, indicating substantial sequence evolution in this region under field conditions. In all cases examined by in situ hybridization, the region concerned is paracentromeric. In contrast, the blot pattern of another probe (M 34) which detects repeated sequences specific to the mouse Y chromosome but outside the sex-determining locus, remains constant between different isolates.

Animals↗
PubMed1988

The relationship between histological grade, oestrogen receptor status, events and survival at 8 years in the NATO ('Nolvadex') trial.

A pathological review was carried out on 600 patients with breast carcinoma entered into the 'Nolvadex' Adjuvant Trial Organisation (NATO) study. The tumours were graded histologically and these results were compared with the oestrogen receptor (ER) status of the tumours, the numbers of recurrences and the length of survival of the patients. It was found that histological grading was predictive both in terms of events and survival, and correlates significantly with oestrogen receptor status; within histological grades I and II, patients receiving 'Nolvadex' had fewer events and deaths compared with patients in the control group. For patients with grade III tumours qualitatively it was in the same direction as the benefit obtained in patients with grade I and II tumours.

Breast Neoplasms↗
PubMed1987

A role for receptors of N-methyl-D-aspartic acid in the discriminative stimulus properties of phencyclidine.

Ketamine and (+)-N-allylnormetazocine ((+)-NANM) were found to generalize in a rat operant drug discrimination paradigm to the interoceptive stimulus induced by phencyclidine (PCP). Intraperitoneal administration of the non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, MK-801, and intracerebroventricular injection of the competitive antagonist, 2-DL-amino-7-phosphonoheptanoic acid (2-APH), also resulted in a dose-dependent generalisation to the PCP discriminative stimulus. The results suggest that NMDA receptor antagonism may play an important role in the mediation of the discriminative stimulus properties of PCP. The low potency of MK-801 and 2-APH to displace [3H](+)-NANM binding in vitro argues against an involvement of the haloperidol-sensitive sigma recognition site in the behaviour.

Animals↗
PubMed1987

Behavioural evidence for an interdependence between GABAA receptors and beta 2-adrenoceptors.

The possibility of a functional interdependence between central GABAA receptors and beta 2-adrenoceptors has been investigated using the ability of both types of agonist to potentiate the tic (head-twitch) response to 5-methoxy-N,N-dimethyltryptamine in the mouse. At a dose which selectively antagonised beta 1- but not beta 2-adrenoceptors, ICI 118,551 abolished the effects of single doses of muscimol, diazepam and pentobarbitone. Conversely, bicuculline abolished the potentiation caused by the beta 2-adrenoceptor agonist procaterol. Thus there is preliminary evidence that these two receptor types do show mutual interdependence.

Animals↗
PubMed1987

Testis development in a mouse with 10% of XY cells.

Two mouse Y-chromosome-related DNA probes were used to show that an aspermic sterile male mouse with small testes contained only approximately 10% of normal XY cells dispersed among normal XX cells. Examination of testis sections by in situ hybridization revealed that XY cells were nonrandomly concentrated in the testis tubules when compared with the interstitial cell population. These observations are discussed in the context of primary sex determination and histological differentiation of the testis.

Animals↗