The dopamine D2 and adenosine A2A receptors: past, present and future trends for the treatment of Parkinson's disease.

Herein, we present an overview of the historic development of drugs for the treatment of Parkinson's disease as well as prospective novel treatment forms based on targeting the dopamine and adenosine receptors. The review includes the development of levodopa, a precursor of the neurotransmitter dopamine, which to date is the most commonly prescribed and most effective drug for controlling the motor symptoms of Parkinson's disease, to more recent studies of the adenosine receptor; a promising target for the treatment of Parkinson's disease due to its intrinsic neuroprotective nature. Ongoing and future drug-based research on the dopamine and adenosine receptors has the advantage of being guided by the improved understanding of receptor topography as well as their functional roles. Breakthroughs such as the first ligand-bound X-ray structure of a selective adenosine A2A receptor antagonist in complex with the adenosine A2A receptor, the discovery of the existence of dopamine D2 homodimers, dopamine D2- adenosine A2A heterodimers and higher order oligomers in addition to technological progress have changed the direction of research in academia and industry and form the pillars for novel and exciting discoveries in this field.

Schizophrenia: a systematic review of the disease state, current therapeutics and their molecular mechanisms of action.

The treatment of schizophrenia, one of the most debilitating mental illnesses, began by the serendipitous discovery of chlorpromazine. Since then, researchers have endeavored to find the cause of the illness but it remains unresolved. As a result, literature on the etiology of schizophrenia is littered with hypotheses and theories that are constantly reviewed, modified and rejected. Two hypotheses, however, have withstood the test of time and serve as the basis for the drug treatment, namely the dopamine and serotonin hypotheses. This review introduces the disease state, summarizes in detail the two leading hypotheses on schizophrenia, presents drugs that are currently available for treatment, and discusses some of the promising drug candidates based on their pre and early clinical trial results.

JL13 has clozapine-like actions on thermoregulatory cutaneous blood flow in rats: Involvement of serotonin 5-HT1A and 5-HT2A receptor mechanisms.

Clozapine is an effective atypical antipsychotic agent, with serious side effects. JL13 [5-(4-methylpiperazin-1-yl)-8-chloropyrido[2,3-b][1,5]benzoxazepine] is a potential new atypical antipsychotic, structurally modified from clozapine to resist oxidation so as to reduce haematological and cardiological side effects. To assess the potential clinical potency of JL13 we tested its action in a newly described animal model based on the ability of clozapine-like agents to affect brain mechanisms controlling sympathetic outflow to thermoregulatory cutaneous vascular beds. We determined whether JL13 has clozapine-like inhibitory actions on alerting-induced falls in tail artery blood flow (sympathetic cutaneous vasomotor alerting responses, SCVARs) in rats, and whether actions on dopamine D(2), and/or 5-HT(1A) receptors are involved in these effects of JL13. The tail artery Doppler flow signal was recorded in conscious freely moving Sprague-Dawley rats before and after alerting stimuli (e.g. cage tap). The percentage fall in flow in response to an alerting stimulus was quantified as a SCVAR index (fall to zero flow implies SCVAR index of 100%, no fall implies 0%). We used pre-treatment with spiperone and WAY100635, before JL13, to assess the role of D(2) and 5-HT(1A) receptors. In addition, the role of 5-HT(2A) receptors in the action of JL13 was assessed by determining whether JL13 prevented and reversed the CNS-mediated tail artery vasoconstricting actions of DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), an agonist at 5-HT(2A) receptors. JL13 (0.0625-5.0mg/kg s.c.) dose-dependently inhibited SCVARs, less potently than clozapine. WAY100635 but not spiperone reduced the inhibition. JL13 prevented and reversed DOI-induced vasoconstriction. Thus JL13 has clozapine-like actions on thermoregulatory cutaneous blood flow, but the drug is 5 times less potent than clozapine. Stimulation of 5-HT(1A) and blockade of 5-HT(2A) receptors may contribute to the effects, but dopamine D(2) receptors are apparently not involved in the action of JL13.

Platensimycin: a promising antimicrobial targeting fatty acid synthesis.

Platensimycin was recently discovered by Merck Research Laboratories and has created considerable interest given its potent antibacterial activity and mode of action. The use of RNA gene-silencing techniques and screening libraries of natural products allowed Merck to find this antibiotic which may have otherwise been missed using conventional methods. Interestingly, platensimycin has shown good activity against a panel of Gram positive organisms which included various resistant strains. Platensimycin works by inhibiting beta-ketoacyl synthases I/II (FabF/B) which are key enzymes in the production of fatty acids required for bacterial cell membranes. So far, a number of groups have explored synthetic strategies for platensimycin and this work has subsequently lead to the synthesis of active analogues. Given its mode of action, it is intriguing as to why Merck themselves patented only a single compound and have not apparently sought to generate further libraries. This review will discuss the origins of platensimycin, its mechanism of action, synthetic schemes and where the future may take us following this fascinating discovery.

Schizophrenia: genesis, receptorology and current therapeutics.

Schizophrenia is a debilitating mental disease affecting approximately 1% of the population worldwide. Since the discovery of the first modern treatment for schizophrenia, chlorpromazine, in 1952 there have been many new structures investigated, only a small fraction of which have resulted in clinically useful drugs. Of these, haloperidol may be regarded as the drug for first line treatment. Since then, clozapine has emerged as the benchmark therapeutic ameliorating positive and negative symptoms and devoid of movement disorders, with its greatest feature being improvement of treatment-resistant patients. However, a major, potential lethal side-effect of clozapine is the induction of agranulocytosis, a blood disorder with unknown mechanism that results in lowered white-blood cell counts and consequent susceptibility to infections. In the 50 years of antipsychotic drug development, several novel theories have evolved that focus on receptor sub-types (serotonin 5-HTsub>2A, dopamine D(2) and D(4)) and the degree to which they need to be selectively attenuated by the drugs. Also of significance is the location of these receptors in the brain in relation to the disease state, the myriad of side-effects associated with antipsychotics and physicochemical properties of antipsychotic molecules relative to models of the drugs and the GPCR receptors involved. The techniques for investigation have shown increasing sophistication and refinement over this period, involving cloned receptors and PET scanning for determination of receptor location, density and binding, and rate constants at receptors. Knowledge of receptor structure, although in its infancy since no membrane bound CNS-receptor has yet been crystallized, is likely to benefit substantially with advances in computer-aided modelling. Overall, these new techniques have resulted in a number of novel antipsychotics such as risperidone, sertindole, olanzapine, seroquel, zotepine and ziprasidone, whose design, synthesis and testing has benefited enormously from the accumulated knowledge base of the past 50 years. In this review, we will provide a comprehensive update of the theories of action and clinical profiles of the latest drugs listed. The following appraisal of the literature will provide the practising medicinal chemist interested in this critical area of research with sufficient insight and understanding, to embark on productive investigations into the design and development of new therapeutic agents devoid of clinically limiting side-effects.

Foodborne Norwalk virus.

On December 6, 1979, three luncheon banquets were served in a New Jersey restaurant. Thirty-eight of 41 members (92.7%) of the first group became ill as did 25 of 31 members (80.6%) of the second group. None of 12 members of the third group were ill. Illness consisted primarily of diarrhea (76%), nausea, (73%), vomiting (67%), cramps (46%) and fever (18%); the median incubation period was 31 hours and median duration 24 hours. The same foods were served to all three groups, except that cole slaw was substituted for a green salad and mixed vegetables for lima beans for the third group. Consumption of green salad was associated with illness (p less than 0.0001). A total of 118 other persons who ate at the restaurant on the same day were interviewed, 60% of whom reported being ill. Green salad was significantly associated with illness for this group at lunch (p = 0.005) and dinner (p = 0.00007). Serologic studies on seven of 12 patients and on one of four exposed controls showed a fourfold or greater rise in antibody titer to Norwalk virus.