Abstract
This article describes our efforts along with recent advances in the development, biological evaluation and clinical proof of concept of small molecule histamine H3 antagonists/inverse agonists. The H3 receptor is a presynaptic autoreceptor within the Class A GPCR family, but also functions as a heteroreceptor modulating levels of neurotransmitters such as dopamine, acetylcholine, norepinephrine, serotonin, GABA and glutamate. Thus, H3R has garnered a great deal of interest from the pharmaceutical industry for the possible treatment of obesity, epilepsy, sleep/wake, schizophrenia, Alzheimers disease, neuropathic pain and ADHD. Within the two main classes of H3 ligands, both imidazole and non-imidazole derived, have shown sufficient potency and specificity which culminated with efficacy in preclinical models for various CNS disorders. Importantly, conserved elements have been identified within the small molecule H3 ligand scaffolds that resulted in a highly predictive pharmacophore model. Understanding of the pharmacophore model has allowed several groups to dial H3R activity into scaffolds designed for other CNS targets, and engender directed polypharmacology. Moreover, Abbott, GSK, Pfizer and several others have reported positive Phase I and/or Phase II data with structurally diverse H3R antagonists/inverse agonists.
Keywords: GPCR, H3, histamine, ADHD, schizophrenia, sleep/wake, obesity, Alzheimer's disease, epilepsy, efficacy, scaffolds, allosteric modulators
Current Topics in Medicinal Chemistry
Title: The Evolution of Histamine H3 Antagonists/Inverse Agonists
Volume: 11 Issue: 6
Author(s): Evan P. Lebois, Carrie K. Jones and Craig W. Lindsley
Affiliation:
Keywords: GPCR, H3, histamine, ADHD, schizophrenia, sleep/wake, obesity, Alzheimer's disease, epilepsy, efficacy, scaffolds, allosteric modulators
Abstract: This article describes our efforts along with recent advances in the development, biological evaluation and clinical proof of concept of small molecule histamine H3 antagonists/inverse agonists. The H3 receptor is a presynaptic autoreceptor within the Class A GPCR family, but also functions as a heteroreceptor modulating levels of neurotransmitters such as dopamine, acetylcholine, norepinephrine, serotonin, GABA and glutamate. Thus, H3R has garnered a great deal of interest from the pharmaceutical industry for the possible treatment of obesity, epilepsy, sleep/wake, schizophrenia, Alzheimers disease, neuropathic pain and ADHD. Within the two main classes of H3 ligands, both imidazole and non-imidazole derived, have shown sufficient potency and specificity which culminated with efficacy in preclinical models for various CNS disorders. Importantly, conserved elements have been identified within the small molecule H3 ligand scaffolds that resulted in a highly predictive pharmacophore model. Understanding of the pharmacophore model has allowed several groups to dial H3R activity into scaffolds designed for other CNS targets, and engender directed polypharmacology. Moreover, Abbott, GSK, Pfizer and several others have reported positive Phase I and/or Phase II data with structurally diverse H3R antagonists/inverse agonists.
Export Options
About this article
Cite this article as:
P. Lebois Evan, K. Jones Carrie and W. Lindsley Craig, The Evolution of Histamine H3 Antagonists/Inverse Agonists, Current Topics in Medicinal Chemistry 2011; 11 (6) . https://dx.doi.org/10.2174/1568026611109060648
DOI https://dx.doi.org/10.2174/1568026611109060648 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Extraction, GC-MS Evaluation and Anti-epileptic Potential of Seeds Ethanolic Extract of Putranjiva roxburghii Wall
Central Nervous System Agents in Medicinal Chemistry A Review on Biological Activities and Chemical Synthesis of Hydrazide Derivatives
Current Medicinal Chemistry Modulation of the FGF14:FGF14 Homodimer Interaction Through Short Peptide Fragments
CNS & Neurological Disorders - Drug Targets The Double Roles of the Prostaglandin E<sub>2</sub> EP2 Receptor in Intracerebral Hemorrhage
Current Drug Targets Mitochondrial Complex I Deficiency in Humans
Current Genomics Neurodevelopment in Schizophrenia: The Role of the Wnt Pathways
Current Neuropharmacology <i>Dichrostachys cinerea</i>: Ethnomedicinal Uses, Phytochemistry and Pharmacological Activities - A Review
The Natural Products Journal Recent Developments in Oxidative Processes in Steroid Chemistry
Current Organic Chemistry Review of the Phytochemistry and Biological Activity of Cissus incisa Leaves
Current Topics in Medicinal Chemistry The Effects of Vitamin B in Depression
Current Medicinal Chemistry Subject Index To Volume 9
Current Medicinal Chemistry Neurocognitive Functioning and Cannabis Use in Schizophrenia
Current Pharmaceutical Design In-person vs. eHealth Mindfulness-based Intervention for Adolescents with Chronic Illnesses: A Pilot Randomized Trial
Adolescent Psychiatry Effects of Brain IKKβ Gene Silencing by Small Interfering RNA on P-Glycoprotein Expression and Brain Damage in the Rat Kainic Acid-Induced Seizure Model
CNS & Neurological Disorders - Drug Targets HLA and TCR Recognition of Medications in Severe Cutaneous Adverse Reactions
Current Immunology Reviews (Discontinued) The Effects of Psychological Stress on Depression
Current Neuropharmacology Effects of Obesity on Vascular Potassium Channels
Current Vascular Pharmacology Synthesis and Structure-Activity Relationship on Anticonvulsant Aryl Semicarbazones
Medicinal Chemistry A Systematic Approach to Hypertensive Urgencies and Emergencies
Current Hypertension Reviews Editorial [Hot Topic: GABA and Glutamate as Targets in Medicinal Chemistry (Guest Editor: Dr. Julianna Kardos)]
Current Topics in Medicinal Chemistry