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Biomedical subjects

G J Riley

Publications and source records attributed to G J Riley.

At least 37 records · Page 2Linked to original sources
PubMed1998

Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors.

Xanomeline [3(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-me thylpyridine] has been reported to act as a functionally selective muscarinic partial agonist with potential use in the treatment of Alzheimer's disease. This study examined the functional activity of xanomeline at 5-HT1 and 5-HT2 receptors in native tissue and/or human cloned receptors. Xanomeline had affinity for muscarinic receptors in rat cortical membranes where the ratio of the displacement affinity of [3H]-Quinuclidinyl benzilate vs that of [3H]-Oxotremorine-M was 16, indicative of partial agonist activity. Radioligand binding studies on human cloned receptors confirmed that xanomeline had substantial affinity for M1, M2, M3, M4, M5 receptors and also for 5-HT1 and 5-HT2 receptor subtypes. Carbachol and xanomeline stimulated basal [35S]-GTPgammaS binding in rat cortical membranes with micromolar affinity. The response to carbachol was attenuated by himbacine and pirenzepine with pA2 of 8.2, 6.9 respectively consistent with the response being mediated, predominantly, via M2 and M4 receptors. Xanomeline-induced stimulation of [35S]-GTPgammaS binding was inhibited by himbacine with an apparent pKb of 6.3, was not attenuated by pirenzepine up to 3 microM and was inhibited by the selective 5-HT1A antagonist WAY100635 with an apparent pKb of 9.4. These data suggest the agonist effect of xanomeline in this tissue is, in part, via 5-HT1A receptors. Similar studies on human cloned receptors confirmed that xanomeline is an agonist at human cloned 5-HT1A and 5-HT1B receptors. In studies using the fluorescent cytoplasmic Ca2+ indicator FLUO-3AM, xanomeline induced an increase in cytoplasmic Ca2+ concentration in SH-SY5Y cells expressing recombinant human 5-HT2C receptors. Atropine antagonized this response, consistent with mediation via endogenously-expressed muscarinic receptors. In the presence of atropine, xanomeline antagonized 5-HT-induced cytoplasmic changes in Ca2+ concentration in cells expressing h5-HT2A, h5-HT2B and h5-HT2c receptors with potencies similar to its affinity at these receptors. These studies indicate that xanomeline is a potent agonist at 5-HT1A and 5-HT1B receptors and an antagonist at 5-HT2 receptor subtypes.

Animals↗
PubMed1997

Design of [R-(Z)]-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2]octane-3-acetonitri le (SB 202026), a functionally selective azabicyclic muscarinic M1 agonist incorporating the N-methoxy imidoyl nitrile group as a novel ester bioisostere.

Loss of cholinergic function is believed to be implicated in the cognitive decline associated with senile dementia of the Alzheimer type (SDAT). The disease is characterized by progressive loss of muscarinic receptors located on nerve terminals while postsynaptic muscarinic M1 receptors appear to remain largely intact. Muscarinic agonists acting directly on postsynaptic receptors offer the prospect of countering the cholinergic deficit in SDAT. This study describes a novel series of azabicyclic muscarinic agonists, which incorporate an oxime ether or modified oxime ether group as an ester bioisostere. Modification of the oxime ether function by the introduction of electron withdrawing groups led to the finding that the (Z)-N-methoxy imidoyl nitrile group serves as a stable methyl ester bioisostere. This culminated in the discovery of the quinuclidinyl N-methoxy imidoyl nitrile R-(+)-(Z)-5g which is a functionally selective muscarinic M1 partial agonist currently in phase III clinical trials for the treatment of SDAT. The selective profile of R-(+)-(Z)-5g can be rationalized in terms of the relative affinity of the compound at muscarinic receptor subtypes, the degree of agonist efficacy, and brain penetrancy.

Alzheimer Disease↗
PubMed1997

Comparison of pneumococcal polysaccharide and CRM197-conjugated pneumococcal oligosaccharide vaccines in young and elderly adults.

Conjugation of carbohydrate antigens to protein carriers significantly improves the immune response to many carbohydrates. In order to evaluate the potential for this approach to improve the performance of pneumococcal vaccine in the elderly, we evaluated pneumococcal polysaccharide-derived oligosaccharides conjugated to cross-reacting material 197 (CRM197) (CRM-OS) in 49 older adults over 60 years of age (median age, 66 years) and compared the results to those from 50 younger adults under age 45 (median age, 27 years). Subjects were randomly assigned to receive licensed 23-valent polysaccharide vaccine (PS) which contain 25 micrograms of polysaccharide per serotype, or 5-valent CRM-OS, which contains 10 micrograms of oligosaccharide per serotype, in double-blind fashion. Both vaccines were associated with moderate local pain on administration. Antibody responses to type 14 were seen in the majority of both younger and older subjects following administration of both CRM-OS and PS, and there was no significant improvement of responses with CRM-OS in either age group. Antibody responses in young adults to the less immunogenic type 6B were seen in only 36% of subjects receiving PS and in 56% of subjects receiving CRM-OS (P = 0.15), and the geometric mean 6B titer 1 month after vaccination was higher in CRM-OS recipients (10.9 versus 3.7 micrograms/ml; P = 0.04). However, 6B responses were poor following the administration of either vaccine to elderly adults and there was no difference between results with CRM-OS and those with PS in this age group. Relatively few subjects developed measurable mucosal immunoglobulin A responses in nasal secretions following administration of either vaccine. Revaccination of CRM-OS recipients with PS at 2 months did not result in significant additional responses to 6B or 14. Though CRM-OS is possibly more immunogenic in young adults, the formulation of the pneumococcal glycoconjugate vaccine used in this study does not appear to offer an advantage to the elderly for types 6B or 14.

Adjuvants, Immunologic↗
PubMed1997

SB 202026: a novel muscarinic partial agonist with functional selectivity for M1 receptors.

The finding that ascending cholinergic systems are severely degenerated in Alzheimer's disease has driven the search for a cholinomimetic therapy. Adverse effects observed with cholinesterase inhibitors and high-efficacy muscarinic agonists led us to design compounds with an improved profile. SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes. In functional models in vitro, SB 202026 caused maximal depolarization of the rat superior cervical ganglion at low concentrations (300 nM) (M1-mediated effect), while producing a lower maximal effect than the high-efficacy agonists oxotremorine-M and carbachol on M2-mediated release of ACh and M3-mediated smooth muscle contraction (guinea pig ileum), respectively. The functional selectivity and partial agonist profile seen in vitro were reflected in vivo through potent cognition-related activity (M1-induced increase in hippocampal EEG power) combined with low efficacy, compared with arecoline or oxotremorine, on induction of bradycardia (M2-mediated response), hypotension (via M3-mediated vasorelaxation) and tremor (thought to be mediated by M3 receptors). The foregoing profile of SB 202026 predicted that cognition-enhancing activity would be achieved at doses below those that initiate undesirable side effects, and this has subsequently been demonstrated in rodents, marmosets and humans.

Acetylcholine↗
PubMed1992

Substituent variation in azabicyclic triazole- and tetrazole-based muscarinic receptor ligands.

The effect of variation of the 1-azabicyclic substituent on the novel 1,2,3-triazol-4-yl-, 1,2,4-triazol-1-yl, tetrazol-5-yl-, and tetrazol-2-yl-based muscarinic receptor ligands has been studied, and the exo-azabicyclic[2.2.1]hept-3-yl substituent was found to give the most potent and efficacious compounds. In addition, variation of the second substituent on 1,2,4-triazol-1-yl- and tetrazol-2-yl-based muscarinic receptor ligands has yielded a series of novel compounds with high potencies and efficacies, ranging from full agonists to antagonists. Small lipophilic electron withdrawing substituents give potent but low efficacy compounds, while small polar electron donating substituents give potent and efficacious compounds. The activity of these compounds is described in terms of a model of the receptor involving lipophilic and hydrogen bonding interactions. These compounds provide muscarinic ligands with high potency and a range of efficacies suitable for testing as candidate drugs in the treatment of Alzheimer's disease.

Alzheimer Disease↗
PubMed1992

Synthesis and muscarinic activities of quinuclidin-3-yltriazole and -tetrazole derivatives.

The synthesis of 15 methyl or unsubstituted 1,2,3-triazoles, 1,2,4-triazoles, and tetrazoles additionally substituted with a 1-azabicyclo[2.2.2]octan-3-yl group is described. The potency and efficacy of these compounds as muscarinic ligands were determined in radioligand binding assays using [3H]oxotremorine and [3H]quinuclidinyl benzilate. Potency and efficacy were found in compounds in which the azole moiety was attached to the azabicyclic ring either through a carbon atom or a nitrogen atom. Electrostatic potential maps of both the C-linked and the novel N-linked series of compounds were calculated. A relationship between position and depth of the electrostatic minima relative to the azabicyclic ring and the potency and efficacy of the compounds was determined.

Animals↗
PubMed1991

Comparison of azabicyclic esters and oxadiazoles as ligands for the muscarinic receptor.

The link between the cognitive deficit associated with Alzheimer type dementia and the loss of cholinergic function in the disease provides a basis for examining muscarinic agonists as potential therapeutic agents. This paper describes the design and synthesis of novel azabicyclic methyl esters as ligands for the muscarinic receptor. Replacement of the methyl ester by a 3-methyl-1,2,4-oxadiazole ring produces potent metabolically more stable muscarinic agonists capable of penetrating the central nervous system. These compounds generally show improved affinity relative to the corresponding methyl esters. 3-Methyl-1,2,4-oxadiazole 7b has an affinity 4 times that of acetylcholine. Receptor affinity is discussed in relation to the size and geometry of the azabicyclic ring and the electronic properties of the heteroaromatic ring.

Aminoquinolines↗
PubMed1981

Plasma tryptophan binding to albumin in unipolar depressives.

The equilibrium binding constants of the interaction of tryptophan with albumin have been determined in plasma samples from both controls and patients suffering from affective disorders. The data corresponded with literature values for both the albumin concentration in plasma and the equilibrium constant for tryptophan binding to albumin. No differences in the equilibrium constants were detected between patients and controls but a small increase in the albumin concentration was noted in the depressives. It was agreed that this rise would be inadequate to lead to a significant effect on free tryptophan levels. Non-esterified fatty acid analysis indicated no differences between patient groups.

Adult↗
PubMed1979

Brain tryptophan metabolism in schizophrenia: a post mortem study of metabolites of the serotonin and kynurenine pathways in schizophrenic and control subjects.

Serotonin (5HT), its chief metabolite 5-hydroxyindoleacetic acid (5 HIAA), its precursor tryptophan, and kynurenine, another metabolite of tryptophan, have been measured in post mortem human brain samples. Concentrations of these metabolites were not found to be significantly different in putamen, hippocampus or temporal cortex from 23 normal subjects compared with 15 subjects in whom a diagnosis of schizophrenia could be restrospectively confirmed. The results have been analysed with respect to cause of death, medication and post mortem changes. Post mortem increases in tryptophan and kynurenine were observed. Some interrelationships between the variables measured within and between the different areas studied are discussed. It is concluded that there is no evidence for a generalised deficit of 5HT in the brain in schizophrenia, nor for gross changes in turnover along the serotonin or kynurenine pathways of tryptophan metabolism in brain.

Aged↗
PubMed1979

Distribution of tryptophan and tyrosine in unipolar affective disorders as defined by multicompartmental analysis.

As requirements for tryptophan for synthesis of protein and 5-hydroxytryptamine were comparable in rat brain, during depletion of tryptophan there could be competition between the two pathways for the amino acid. This implied that tryptophan should be rate-limiting for protein synthesis and this was found in the short term when concentrations of the amino acid were reduced in rats. Multicompartmental studies of tryptophan and tyrosine in controls and patients subject to unipolar depression defined two main pools of the amino acid provisionally assigned to extracellular and intracellular spaces. For tyrosine, mean values for the extracellular space were comparable to those of controls. The concentration of tyrosine was low in the intracellular space in both depressed and recovered patients, but the raised fractional clearance rates for this compartment during depression had returned to normal on remission. Plasma tryptophan concentrations were significantly reduced in depression with intermediate values after recovery. This suggested that the procedure used may have been mildly stressful and that this had evoked an idiosyncratic response to the stress in the depressed patients, which was characterized by inability to maintain concentrations of this amino acid in plasma. The findings for both amino acids may have a bearing on the aetiology of unipolar affective disorder.

Adult↗
PubMed1979

Multicompartmental analysis of amino acids. III. Tyrosine in affective disorder.

Multicompartmental studies of tyrosine in patients suffering from affective disorders and controls gave estimates of 2 major pools of amino acid, together with the associated fractional clearance rates and fluxes. The 2 pools were considered provisionally to represent extracellular and intracellular tyrosine. The concentration of tyrosine in plasma (representing the extracellular pool) and fractional clearance rates from this compartment were normal in ill and recovered patients. The observed abnormalities were confined to the intracellular compartment and consisted of low concentrations of tyrosine in both depressed and recovered patients. In addition, fractional clearance rates from the intracellular compartment were raised in the depressed patients but had returned to normal after recovery. A comparison of these data with those of a similar study of tryptophan described previously suggested that alterations in compartmental volume or dietary differences could not explain the 2 sets of findings. The disturbances in tryptophan metabolism in unipolar affective disorder had led to reduced amounts of this amino acid in the extracellular space. In contrast, the concentration of tyrosine in this compartment was normal, presumably as a result of a metabolic adjustment to the lower amounts found in the intracellular pool. The presence of illness-dependent and illness-independent alterations in tyrosine metabolism in unipolar affective disorder, together with the earlier findings for tryptophan, may have a bearing on the aetiology of the illness.

Adult↗
PubMed1979

Monoamine mechanisms in chronic schizophrenia: post-mortem neurochemical findings.

Dopamine and its metabolites homovanillic acid and dihydroxyphenylacetic acid, noradrenaline, serotonin and its metabolite 5-hydroxyindoleacetic acid, and tryptophan and its metabolite kynurenine have been assayed in 9 schizophrenic and 10 control brains, together with the monoamine-related enzymes tyrosine hydroxylase monoamine oxidase, dopamine-beta-hydroxylase, and catechol-o-methyl-transferase. In schizophrenic brains dopamine, noradrenaline and serotonin were significantly increased in some areas of corpus striatum, but there were no significant changes in enzyme activity or monoamine metabolite concentrations in any of the brain areas examined. The findings are not consistent with theories that serotonin or noradrenaline stores are grossly depleted or noradrenaline neurones have degenerated, or that monoamine oxidase activity is abnormal, in schizophrenia, and provide no direct support for the hypothesis that dopamine neurones are overactive.

Aged↗
PubMed1978

The activities of brain dopamine-beta-hydroxylase and catechol-O-methyl transferase in schizophrenics and controls.

It has been suggested that deterioration of central noradrenergic pathways may be responsible for the production of certain schizophrenic symptoms, and that such a degeneration might be reflected in lowered dopamine-beta-hydroxylase (DBH) activity in the brains of schizophrenics. The present study revealed that in rats lowered DBH activity was a sensitive index of noradrenergic degeneration. In the postmortem brains of 12 controls and 12 schizophrenics, however, no significant difference in DBH activity between controls and schizophrenics was found. DBH activity was relatively unstable postmortem and adversely affected by neuroleptic drugs, and these factors may have contributed to the previous finding of lowered DBH activity in the brains of schizophrenics. The activity of catechol-O-methyl transferase, which has also been previously reported as low in the brains of schizophrenics, was found to be no different in the controls of the present study.

Animals↗