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Biomedical subjects

David R Thomas

Publications and source records attributed to David R Thomas.

At least 37 records · Page 2Linked to original sources
PubMed2004

Distribution of 5-HT7 receptors in the human brain: a preliminary autoradiographic study using [3H]SB-269970.

The distribution of the 5-HT7 receptor was analyzed using the selective 5-HT7 receptor antagonist radioligand [3H]SB-269970 and human brain whole hemisphere autoradiography. The results indicated that 5-HT7 receptors are most abundantly localized in the anterior thalamus and in the dentate gyrus. Other regions containing intermediate levels of 5-HT7 receptors included the hypothalamus, anterior cingulate gyrus, hippocampus, amygdala and certain brainstem nuclei. The distribution pattern obtained in this study supports the involvement of this receptor subtype in affective behavior and cognition.

Adult↗
PubMed2004

Cloning and pharmacological characterisation of the guinea pig 5-ht5A receptor.

The guinea pig 5-hydroxytryptamine(5A) (gp5-ht(5A)) receptor was cloned from guinea pig brain using degenerate polymerase chain reaction (PCR) and shows 88%, 85% and 84% amino acid sequence identity versus the human, rat and mouse 5-ht(5A) receptors, respectively. The receptor was transiently expressed in human embryonic kidney (HEK) 293 cells. [(3)H]-Lysergic acid diethylamide (LSD) bound saturably to gp5-ht(5A)/HEK293 membranes with a K(d) of 2.3+/-0.1 nM and B(max) of 15.7+/-3.4 pmol/mg protein. The receptor binding profile, determined by competition with [(3)H]LSD, correlated well with that for the human 5-ht(5A) receptor. 5-HT stimulated [(35)S]GTPgammaS binding to gp5-ht(5A)/HEK293 membranes (pEC(50) 8.1+/-0.2), and the response was surmountably antagonised by methiothepin and ritanserin, giving apparent pK(B) values of 8.0 and 7.2, respectively. The 5-HT response was absent using membranes prepared from gp5-ht(5A)/HEK293 cells pretreated with pertussis toxin (PTX). These data suggest that the gp5-ht(5A) receptor couples to G(i)-proteins in this expression system and shows a similar pharmacological profile to that for the human 5-ht(5A) receptor.

Amino Acid Sequence↗
PubMed2004

Vitamins in health and aging.

The use of various dietary supplements, including vitamins, to prevent or delay disease or aging rests for the most part on epidemiological associations. It does appear from these data that a diet rich in vitamins is associated with a tendency to improved health; however, the results from controlled trials are dismal. The discrepancy between different types of studies is probably explained by the fact that dietary composition and supplement use is a component in a cluster of healthy behaviors. An alternative hypothesis is that there are as-yet-unknown essential organic compounds in certain foods. The most prudent approach is to recommend a daily intake of fruits and vegetables as a likely source of essential nutrients. Failing compliance with a natural source of essential nutrients, and in populations at high risk of vitamin deficiency, vitamin supplements should be encouraged.

Aged↗
PubMed2004

Pharmacologic management of urinary incontinence.

Urinary incontinence is a highly prevalent and difficult to treat medical condition. For those who are affected, urinary incontinence produces profound modifications in lifestyle and perceived quality of life. Pharmacologic therapy clearly is beneficial for most types of urinary incontinence. The low therapeutic success of current treatments and obnoxious side effects, however, limit patient satisfaction and compliance. There is a considerable need for improved therapeutic options to treat this devastating condition.

Adrenergic Antagonists↗
PubMed2004

GABAergic modulation of 5-HT7 receptor-mediated effects on 5-HT efflux in the guinea-pig dorsal raphe nucleus.

5-HT(7) receptor mRNA and protein are localised in the dorsal raphe nucleus (DRN) on non-serotonergic neurones. The effect of 5-HT(7) receptor antagonism on 5-HT efflux was measured from guinea-pig DRN slices, using the technique of fast cyclic voltammetry. The 5-HT(7) receptor antagonist, SB-269970-A, significantly inhibited 5-HT efflux. The GABA(A) receptor agonist, muscimol, significantly inhibited 5-HT efflux, to a similar degree as SB-269970-A. In contrast, the GABA(A) receptor antagonist, bicuculline, significantly increased 5-HT efflux and attenuated the muscimol-induced inhibition. The muscimol and SB-269970-A effects were not additive and in the presence of bicuculline the SB-269970-A-induced inhibition of 5-HT efflux was attenuated. These data suggest that 5-HT(7) receptor antagonist-induced inhibition of 5-HT efflux occurs indirectly via activation of GABA(A) receptors. That is, 5-HT(7) receptors may be located on GABA interneurones and when activated decrease GABA release and hence decrease the inhibitory tone on 5-HT neurones, increasing 5-HT efflux in the DRN. Therefore, in the presence of GABAergic tone 5-HT(7) receptor antagonists would decrease 5-HT release from the DRN.

Animals↗
PubMed2004

5-HT7 receptors.

Following the cloning of the 5-HT(7) receptor in 1993, studies to investigate 5-HT(7) receptor function in native tissues focused on identifying functional correlates that matched the pharmacological profile determined for the cloned receptor. Studies in peripheral tissues established that the 5-HT(7) receptor mediates the relaxation of smooth muscle, including the gastrointestinal tract and cardiovascular systems. Although a number of studies provided preliminary evidence for a role for the 5-HT(7) receptor in the circadian pacemaker function of the suprachiasmatic nucleus (SCN), additional studies to investigate 5-HT(7) receptor function in other brain regions have, until recently, been hindered by the absence of 5-HT(7) receptor-selective ligands. More recently, a number of 5-HT(7) receptor-selective antagonists including, SB-269970-A and SB-656104-A have been developed. Studies utilising these compounds suggest that the 5-HT(7) receptor modulates neuronal function in a number of brain areas including the hippocampus and thalamus. In turn, these findings suggest that 5-HT(7) receptor-selective ligands might prove therapeutically useful for the treatment of psychiatric disorders. In this respect there is increasing evidence to suggest that the 5-HT(7) receptor plays a role in the control of both circadian rhythms and sleep and might therefore represent a therapeutic target for the treatment of those disorders in which disturbances in circadian rhythms and sleep architecture are thought to be contributory factors. Furthermore, there is evidence to suggest that the receptor may play a role in other CNS disorders including, anxiety, cognitive disturbances and also migraine probably via both peripheral and central mechanisms. Although further studies are required to confirm the potential role of the receptor in such disorders, findings to date suggest there are exciting opportunities for the development of novel therapeutic agents acting either selectively at the 5-HT(7) receptor or whose profile of action includes an interaction with this receptor.

Animals↗
PubMed2003

A novel ergot alkaloid as a 5-HT(1A) inhibitor produced by Dicyma sp.

In the course of a search for small-molecule inhibitors of 5-hydroxytryptamine receptors we have identified a novel ergoline derivative (1) from the fungal culture of Dicyma sp. This compound has a pK(i) of 10.2 versus the 5-hydroxytryptamine(1A) receptor subtype. The structure was elucidated by extensive NMR spectroscopy and mass spectrometry.

Animals↗
PubMed2003

Identification of a novel series of selective 5-HT7 receptor antagonists.

Novel 5-HT(7) receptor antagonists containing the benzocycloheptanone core were identified from high throughput screening. Molecular modelling and SAR studies have converted these intractable hits into a more potent, selective and tractable series, exemplified by compound (25), SB-691673.

Cytochrome P-450 Enzyme System↗
PubMed2003

Dietary factors in atherogenesis.

Emerging evidence continues to increase our awareness of the complexity of pathologic processes involved in atherogenesis. Dietary modulation exclusively targeting cholesterol consumption is rapidly becoming an archaic mode of intervention as alternative theories of atherogenesis evolve. The interaction of nutrients that occurs with different dietary patterns has been the subject of intense research. Similarly, the effect of diet on vascular reactivity, lipid metabolic kinetics, and antioxidant potential has enormous implications for therapeutic modalities targeting atherosclerosis. Many dietary strategies aimed at inhibiting and preventing atherogenesis have resulted from ongoing research. Consensus opinions extrapolated from available data have also emerged. Regardless, the precise role of dietary modulation in atherogenesis is yet to be fully elucidated. This article reviews recent evidence relating to the interface between dietary factors and biologic models of atherogenesis. Clinical implications and practical applications are also discussed.

Animals↗
PubMed2003

Medications and sexual function.

There seems to be a reluctance to self-report sexual dysfunction during clinical interviews. The rate of reported sexual dysfunction increases when information is sought aggressively in the clinical interview. The relationship to a specific therapeutic agent, however, can be clouded by the patient's perception and coexisting morbidity. Most of the data relating sexual dysfunction to specific drugs are anecdotal. The strongest proof of a casual effect is improvement in sexual function after withdrawal of the medication. Most of the adverse sexual effects of commonly used medications can be predicted from a simplified understanding of the human sexual response and physiologic mediators. Alternative therapeutic agents can be substituted by understanding these physiologic mechanisms and a careful clinical interview. Although polypharmacy is a problem for older persons, in some cases sildenafil can be used to correct drug-induced impotence.

Drug-Related Side Effects and Adverse Reactions↗
PubMed2003

SB-656104-A, a novel selective 5-HT7 receptor antagonist, modulates REM sleep in rats.

1 (6-((R)-2-[2-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-ethyl]-pyrrolidine-1-sulphonyl)-1H-indole hydrochloride) (SB-656104-A), a novel 5-hydroxytryptamine (5-HT(7)) receptor antagonist, potently inhibited [(3)H]-SB-269970 binding to the human cloned 5-HT(7(a)) (pK(i) 8.7+/-0.1) and 5-HT(7(b)) (pK(i) 8.5+/-0.2) receptor variants and the rat native receptor (pK(i) 8.8+/-0.2). The compound displayed at least 30-fold selectivity for the human 5-HT(7(a)) receptor versus other human cloned 5-HT receptors apart from the 5-HT(1D) receptor ( approximately 10-fold selective). 2 SB-656104-A antagonised competitively the 5-carboxamidotryptamine (5-CT)-induced accumulation of cyclic AMP in h5-HT(7(a))/HEK293 cells with a pA(2) of 8.5. 3 Following a constant rate iv infusion to steady state in rats, SB-656104 had a blood clearance (CL(b)) of 58+/-6 ml min(-1) kg(-1) and was CNS penetrant with a steady-state brain : blood ratio of 0.9 : 1. Following i.p. administration to rats (10 mg kg(-1)), the compound displayed a t(1/2) of 1.4 h with mean brain and blood concentrations (at 1 h after dosing) of 0.80 and 1.0 micro M, respectively. 4 SB-656104-A produced a significant reversal of the 5-CT-induced hypothermic effect in guinea pigs, a pharmacodynamic model of 5-HT(7) receptor interaction in vivo (ED(50) 2 mg kg(-1)). 5 SB-656104-A, administered to rats at the beginning of the sleep period (CT 0), significantly increased the latency to onset of rapid eye movement (REM) sleep at 30 mg kg(-1) i.p. (+93%) and reduced the total amount of REM sleep at 10 and 30 mg kg(-1) i.p. with no significant effect on the latency to, or amount of, non-REM sleep. SB-269970-A produced qualitatively similar effects in the same study. 6 In summary, SB-656104-A is a novel 5-HT(7) receptor antagonist which has been utilised in the present study to provide further evidence for a role for 5-HT(7) receptors in the modulation of REM sleep.

Animals↗