Harry Ralph Howard

Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile

Ziprasidone is a novel antipsychotic agent with a unique combination of pharmacological activities at human receptors. Ziprasidone has high affinity for human 5-HT receptors and for human dopamine D(2) receptors. Ziprasidone is a 5-HT(1A) receptor agonist and an antagonist at 5-HT(2A), 5-HT(2C) and 5-HT(1B/1D) receptors. Additionally, ziprasidone inhibits neuronal uptake of 5-HT and norepinephrine comparable to the antidepressant imipramine. This unique pharmacological profile of ziprasidone may be related to its clinical effectiveness as a treatment for the positive, negative and affective symptoms of schizophrenia with a low propensity for extrapyramidal side effects, cognitive deficits and weight gain.

Chapter 5. Novel Antipsychotics

Publisher Summary This chapter describes the novel atypical anti-psychotic agents that are used in treating schizophrenia. Use of such agents is also popular because of their reduced side effects compared to other similar agents. Newly identified dopamine receptors (D3, D4, D5), which were further characterized, has included the first autoradiographic visualization of D3 receptors in rat and human brain. The D4 receptor has been found to exist as several polymorphic variants that may explain the genetic range of susceptibility to schizophrenia and/or varied individual response to anti-psychotics. Researchers have measured the levels of messenger RNA (mRNA) for D1, D2, D3, and D5 receptors in the rat brain after neuroleptic treatment. Clinical trials with roxindole, a D2 autoreceptor agonist, showed efficacy in a group of schizophrenic patients with primary negative symptoms, whereas, results with SDZ-HDZ912 have been less conclusive. The virtues of this atypical anti-psychotic continue to be extolled. Debate on the novel mechanisrn(s) of action of clozapine continues: its superior efficacy has been attributed to interactions with a variety of receptor sites in the CNS and this list has been expanded to include 5HT 1c , D 4 , and glutamate. The chapter also discusses the role of serotonine antagonists, sigma receptors, neurokinin, and others. Several additional receptors have been proposed as having a potential role in the alleviation of psychotic symptoms. The genetic factor in the development of schizophrenia has been further emphasized as has the incidence of the disease because of prior exposure to viral pathogens. Other biological findings like the interaction of neuroleptics with the CNS receptors utilizing positron emission tomography (PET) and magnetic resonance imaging (MRI) techniques, and molecular modeling studies have also got their significance.

Agents for attention-deficit hyperactivity disorder – an update

Attention-deficit hyperactivity disorder (ADHD) is a psychological disorder affecting children and adolescents, whose symptoms often persist into the adult years, and is often effectively treated with stimulants. Recently, non-stimulant medications that demonstrate better toleration and administration have been studied in clinical settings and some have been approved. Yet, there continues to be strong emphasis in many research groups to find even more efficacious and safer alternatives, especially with substances that function through novel, non-stimulatory mechanisms. A review of the progress achieved during the last 4 years, determined from the publication of patents and patent applications, is presented.

Synthesis of conformationally restricted substance P antagonists

Reaction of CP-99,994 (1) with benzyl chloromethyl ether under basic conditions produced the novel 1,6-diazabicyclo[3.2.1]octane system in good yield; analogs containing this nucleus display high binding affinity for substance P receptors. The ethylene homologue of 1a, diamine 7, shows enhanced inhibitory activity and may more closely approximate the binding conformation of 1a at the NK1 receptor.

Antipsychotic drugs: recent developments and novel agents

A sizeable number of new chemical entities designed to effectively treat acute and chronic schizophrenic behaviour have been disclosed in the patent literature during 1995 and 1996 and are discussed in this update. While the majority of these cases involve compounds which display high affinity for CNS dopamine receptors (particularly D2 and D4 subtypes), many others claim the ability to produce efficacy through indirect regulation of dopaminergic activity, e.g., via serotonin selective mechanisms. Still others offer the possibility of relief through interactions with less obvious receptors including neurokinin, glutamate and nicotinic systems. Many of these inventions also claim the potential for clozapine-like ‘atypical’ profiles, but with the advantage of being free from the potential for inducing blood disorders, like agranulocytosis, which could limit market exposure of a commercial product. The gradual emergence and success of new antipsychotic drugs, including risperidone, which combine potent dopam...

7-Phenylsulfonyl-tetrahydro-3-benzazepine derivatives as antipsychotic agents

A series of structurally related arylsulfonyl substituted 3-benzazepines displaying dopamine and serotonin antagonist activities, with pKi values in the range of 6.7 – 8.8, are disclosed in three applications from Glaxo. These compounds are claimed to have potential for the treatment of schizophrenia and other CNS disorders, either alone or in combination with other medications. WO2005051399 describes the synthesis and physicochemical properties of 7-[4-(3-fluoro-4-methylbenzyl)-benzensulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and its tosylate.

Therapeutic agents for attention deficit disorders

Attention deficit hyperactivity disorder (ADHD) is a syndrome that affects young children, manifesting itself through inappropriate behaviours and learning difficulties and persisting in many instances into adulthood. Treatment with stimulants, such as methylphenidate, is often sufficient but carries with it some risk for the emergence of unwanted side effects that can influence compliance, particularly with children. Newer agents and novel mechanisms for achieving control of the symptoms associated with ADHD are proposed in recent patents and applications and are presented in this review.Attention deficit hyperactivity disorder (ADHD) is a syndrome that affects young children, manifesting itself through inappropriate behaviours and learning difficulties and persisting in many instances into adulthood. Treatment with stimulants, such as methylphenidate, is often sufficient but carries with it some risk for the emergence of unwanted side effects that can influence compliance, particularly with children. Newer agents and novel mechanisms for achieving control of the symptoms associated with ADHD are proposed in recent patents and applications and are presented in this review.

1,2,3,4-tetrasubstituted isoquinoline acetic acids

Abstract Differentially tetrasubstituted isoquinolines are now conveniently prepared by rearrangement of the readily obtainable indanones.

Fused thiazole derivatives having affinity for the histamine H3 receptor

A group of structurally related thiazoloazepines displaying high affinity for histamine receptors of the H3 subtype, with pKi values in the range of 7.5 – 9.5, are disclosed in the latest of a series of such applications from Glaxo. These compounds have potential utility in the treatment of CNS disorders, in particular for the improvement of cognitive deficits and alleviation of some symptoms of Alzheimer’s disease, when administered either alone or in combination with other psychotherapeutic agents, for example, muscarinic M1 agonists or acetylcholinesterase inhibitors.

4-Arylpiperidine derivatives and uses thereof for preparing a medicament for the treatment of CNS disorders: University of Pisa: WO2006106432

A novel series of 4-arylpiperidines and their salts, as well as their use in the treatment of CNS disorders, that is, depression, are disclosed. These compounds function as serotonin transporter (SERT) inhibitors and demonstrate significant activity and selectivity for SERT versus other receptors and monoamine transporters.