Biomedical subjects
Publications and source records attributed to Jeannette M Watson.
Investigation of halogen substitution in lead compound 1 has led to the identification of analogues which combine high affinity for 5-HT(1A) receptors and potent serotonin reuptake inhibitory activity. Several compounds show an improved selectivity over 5-HT(1B) and 5-HT(1D) receptors and a superior pharmacokinetic profile in the rat.
The novel 8-piperazinyl-2,3-dihydropyrroloisoquinoline template was synthesized in nine steps. The template was N-substituted to give a series of compounds showing binding to human cloned 5-HT1A, 5-HT1B and 5-HT1D receptors with pKi's greater than 9 and selectivities up to 1000-fold against other serotonin, dopamine and adrenergic receptors. Several compounds were shown to possess weak partial agonist activity in cloned receptors, which translated to antagonism in in vitro studies.
A series of 5-(piperidinylethyloxy)quinoline 5-hydroxytryptamine(1D) (5-HT(1D)) receptor antagonists have been discovered from elaboration of the series of dual 5-hydroxytryptamine(1)-selective serotonin reuptake inhibitors (5HT(1)-SSRIs) reported previously. This is the first report of highly potent, selective antagonists for the 5-HT(1D) receptor, which represents an extremely useful set of pharmacological tools for further understanding the roles of the 5-HT(1) receptor subtypes.
Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT(1A) receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT(1A/1B/1D) receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pK(i)8.2). This compound also had good oral bioavailability and brain penetration in the rat.
At their clinical doses, current antipsychotic agents share the property of both dopamine D(2) and D(3) receptor blockade. However, a major disadvantage of many current medications are the observed extrapyramidal side-effects (EPS), postulated to arise from D(2) receptor antagonism. Consequently, a selective dopamine D(3) receptor antagonist could offer an attractive antipsychotic therapy, devoid of the unwanted EPS. Using SAR information gained in two previously reported series of potent and selective D(3) receptor antagonists, as exemplified by the 2,3,4,5-tetrahydro-1H-3-benzazepine 10 and the 2,3-dihydro-1H-isoindoline 11, a range of 7-sulfonyloxy- and 7-sulfonylbenzazepines has been prepared. Compounds of this type combined a high level of D(3) affinity and selectivity vs D(2) with an excellent pharmacokinetic profile in the rat. Subsequent optimization of this series to improve selectivity over a range of receptors and reduce cytochrome P450 inhibitory potential gave trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxidiazolyl))phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (58, SB-414796). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and is CNS penetrant in the rat. Subsequent evaluation in the rat has shown that 58 preferentially reduces firing of dopaminergic cells in the ventral tegmental area (A10) compared to the substantia nigra (A9), an observation consistent with a prediction for atypical antipsychotic efficacy. In a separate study, 58 has been shown to block expression of the conditioned place preference (CPP) response to cocaine in male rats, suggesting that it may also have a role in the treatment of cue-induced relapse in drug-free cocaine addicts.
We have recently shown that UDP-glucose, and some related UDP-sugars, are potent agonists of the novel G protein-coupled receptor GPR105 (recently re-named P2Y(14)). GPR105 is widely expressed throughout many brain regions and peripheral tissues of human and rodents, and couples to a pertussis toxin-sensitive G protein. To further characterise the role of GPR105, we demonstrate by immunohistochemistry with receptor-specific antiserum that GPR105 protein is widely distributed throughout the post mortem human brain where it is localised to glial cells, and specifically co-localises with astrocytes. Using quantitative RT-PCR we also show that GPR105 mRNA exhibits a restricted expression profile in an array of human cell lines and primary cells, with prominent expression detected in immune cells including neutrophils, lymphocytes, and megakaryocytic cells. To investigate the G protein selectivity of GPR105, we used chimeric Galpha subunits (Galpha(qi5), Galpha(qo5), and Galpha(qs5)) and an intracellular Ca(2+) mobilisation assay to demonstrate that GPR105 couples to Galpha subunits of the G(i/o) family but not to G(s) family proteins or to endogenous G(q/11) proteins in HEK-293 cells. Finally, we show that expression of GPR105 mRNA in the rat brain is up-regulated by immunologic challenge with lipopolysaccharide. Based on these observations, we propose that G(i/o)-coupled GPR105 might play an important role in peripheral and neuroimmune function in response to extracellular UDP-sugars.
Serotonin reuptake inhibitors have proved to be a very effective treatment for depression and have strengthened the hypothesis that impaired 5-hydroxytryptamine (5-HT) neurotransmission may contribute to the underlying cause of depressive disorders. Extensive research has been carried out to investigate other 5-HT targets associated with the disease and studies involving combination treatments with selective serotonin reuptake inhibitors and 5-HT(1A) receptor ligands are currently being carried out in the clinic. Whether other 5-HT receptor subtypes are involved in the aetiology of depression remains to be seen.
Although the precise neurochemical imbalances in depression are still unknown, a role for the neurotransmitter 5-hydroxytryptamine (serotonin) has been implicated since the identification of the first effective antidepressants, imipramine and iproniazid. This led to the development of the selective serotonin re-uptake inhibitors which are widely used in the treatment of depression and depressive disorders, including generalised anxiety disorder, social phobia, obsessive compulsive disorder etc. Studies involving chronic administration in rats led to the hypothesis that the different classes of antidepressant treatment produce a common neuroadaptive change, namely an enhancement of serotonin neurotransmission, albeit via different pre and postsynaptic mechanisms. From this, it was suggested that serotonin antagonists should induce similar neuroadaptive changes, either directly or through a potentiation of other antidepressant agents. Here, the profiles of novel serotonin antagonists currently in preclinical development are reviewed and their therapeutic potential is assessed.