Missale, Cristina, S. Russel Nash, Susan W. Robinson, Mohamed Jaber, and Marc G. Caron. Dopamine Receptors: From Structure to Function. Physiol. Rev. 78: 189–225, 1998. — The diverse physiological actions of dopamine are mediated by at least five distinct G protein-coupled receptor subtypes. Two D1-like receptor subtypes (D1 and D5) couple to the G protein Gs and activate adenylyl cyclase. The other receptor subtypes belong to the D2-like subfamily (D2 , D3 , and D4) and are prototypic of G protein-coupled receptors that inhibit adenylyl cyclase and activate K+ channels. The genes for the D1 and D5 receptors are intronless, but pseudogenes of the D5 exist. The D2 and D3 receptors vary in certain tissues and species as a result of alternative splicing, and the human D4 receptor gene exhibits extensive polymorphic variation. In the central nervous system, dopamine receptors are widely expressed because they are involved in the control of locomotion, cognition, emotion, and affect as well as neuroendocrine s...

Dopamine Receptors: From Structure to Function

DOPAMINE receptors belong to the family of G protein-coupled receptors. On the basis of the homology between these receptors, three different dopamine receptors (D1,D2,D3) have been cloned1–7. Dopamine receptors are primary targets for drugs used in the treatment of psychomotor disorders such as Parkinson's disease and schizophrenia8,9. In the management of socially withdrawn and treatment-resistant schizophrenics, clozapine10 is one of the most favoured antipsychotics because it does not cause tardive dyskinesia11. Clozapine, however, has dissociation constants for binding to D2 and D3 that are 4 to 30 times the therapeutic free concentration of clozapine in plasma water12,13. This observation suggests the existence of other types of dopamine receptors which are more sensitive to clozapine. Here we report the cloning of a gene that encodes such a receptor (D4). The D4 receptor gene has high homology to the human dopamine D2 and D3 receptor genes. The pharmacological characteristics of this receptor resembles that of the D2 and D3 receptors, but its affinity for clozapine is one order of magnitude higher. Recognition and characterization of this clozapine neuroleptic site may prove useful in the design of new types of drugs.

Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine.

A rating scale for drug-induced akathisia has been derived that incorporates diagnostic criteria for pseudoakathisia, and mild, moderate, and severe akathisia. It comprises items for rating the observable, restless movements which characterise the condition, the subjective awareness of restlessness, and any distress associated with the akathisia. In addition, there is an item for rating global severity. A standard examination procedure is recommended. The inter-rater reliability for the scale items (Cohen's kappa) ranged from 0.738 to 0.955. Akathisia was found in eight of 42 schizophrenic in-patients, and nine had pseudoakathisia, where the typical sense of inner restlessness was not reported.

A rating scale for drug-induced akathisia

Actions of acetylcholine in the periphery are the result of activation of either the ionotropic nicotinic receptor or the metabotropic muscarinic receptor. In the mammalian central nervous system (CNS)c, both nicotinic and muscarinic receptor subtypes are present on neurons, although there is as yet

https://pharmrev.aspetjournals.org/content/pharmrev/50/2/279.full.pdf

International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors

Neurocircuitry of Mood Disorders

A CP-103, N-(4-flurophenylmethyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy) phenylmethyl)carbamide (2R,3R)-dihydroxybutanedioate (2:1), is a potent inverse agonist at serotonin 5-HT2A receptors currently being developed as a novel antipsychotic drug. In a phase I clinical study, ACP103 was found to be safe and well tolerated at single oral doses ranging from 20 to 300 mg and multiple doses up to and including 100 mg daily for 14 days in healthy volunteers. The first pharmacokinetic study in humans was conducted using an oral solution. Administration of this oral solution resulted in a bitter taste and was not well tolerated. In that first study, single doses greater than 50 mg were administered nasogastrically to avoid the local intolerance. ACP-103 was administered in powder-filled capsules for the multiple-dose study. Subsequently, ACP-103 was formulated in an immediate-release coated tablet. The purpose of the present study was to compare the pharmacokinetics after administration of the formulated coated tablet to those after administration of the solution of ACP-103. Furthermore, the effects of food on the pharmacokinetics of ACP-103 after a single oral administration were evaluated in healthy male subjects.

The effects of food on the pharmacokinetics of a formulated ACP-103 tablet in healthy volunteers.

Parkinson's disease (PD) is a movement disorder characterized by progressive degeneration of central dopaminergic systems. Current therapies designed to augment dopaminergic neurotransmission effectively treat the motoric aspects of the disease, however, with prolonged use, they produce a range of treatment-limiting side effects. Of these, neuropsychiatric abnormalities including hallucinosis and psychosis are common, disabling and refractory to most current therapies. This review describes the clinical syndrome of psychosis in PD and data regarding the efficacy and tolerability of existing antipsychotic agents, and presents the scientific rationale for the development of serotonin 2A receptor inverse agonists as potential therapeutic agents for treatment-induced psychosis of PD.

Psychosis of Parkinson's disease: serotonin 2A receptor inverse agonists as potential therapeutics.

Erratum: Evidence for a model of agonist-induced activation of 5-hydroxytryptamine 2A serotonin receptors that involves the disruption of a strong ionic interaction between helices 3 and 6 (Journal of Biological Chemistry (2002) 277 (11441-11449))

ACP-103, A 5-HT2A receptor inverse agonist, a novel potential treatment for psychosis

Background and objectives: A number of recent studies surveying single nucleotide polymorphisms within the exonic regions of human genes have revealed a significant number of such variants, including many non-synonymous variants. This highlights the need to directly identify, within individual clinically well-defined patients, those variants that alter protein function as well as structure. We report on the development of a novel phenotypic screening process that combines high-throughput molecular cloning techniques with functional expression utilizing the cell-based assay R-SAT. Methods: We applied the phenotypic screening process to an analysis of the m1 muscarinic acetylcholine receptor (CHRM1) gene in a cohort of 74 individuals, including 48 diagnosed with neurodegenerative disease, primarily Alzheimer disease, who have been stratified according to their clinical response to the acetylcholinesterase inhibitor donepezil. Phenotypic screening of the CHRM1 gene involved PCR-based amplification from genomic DNA and heterologous expression in mammalian cells. Results: Phenotypic screening yielded functional responses to the agonist carbachol displaying a mean potency (−pEC50 ± standard deviation) of 5.8 ± 0.2, which did not differ from that observed with expression of the wild-type receptor gene (6.0 ± 0.3). No altered levels of constitutive receptor activity were observed. Dideoxy sequencing did not reveal any non-synonymous variants in the coding exon of this gene within this clinical cohort, while detecting three synonymous variants. Conclusion: The results confirm that the m1 receptor gene (CHRM1) is not highly polymorphic in the human population, suggesting that genetic variation within the coding exon of this gene is not a contributing factor to the clinical variability observed during treatment of dementia with cholinergic enhancement therapies.

David M. Weiner

Papers

The effects of food on the pharmacokinetics of a formulated ACP-103 tablet in healthy volunteers.

Psychosis of Parkinson's disease: serotonin 2A receptor inverse agonists as potential therapeutics.

Erratum: Evidence for a model of agonist-induced activation of 5-hydroxytryptamine 2A serotonin receptors that involves the disruption of a strong ionic interaction between helices 3 and 6 (Journal of Biological Chemistry (2002) 277 (11441-11449))

ACP-103, A 5-HT2A receptor inverse agonist, a novel potential treatment for psychosis

Functional Screening of Drug Target Genes