Abstract
Structure-activity relationships of a 4-aminoquinoline MCH-1R antagonist lead series were explored by synthesis of analogs with modifications at the 2-, 4- and 6-positions of the original HTS hit. Improvements to the original screening lead were made by addition of lipophilic groups at the 2-position and biphenyl, cyclohexyl phenyl and hydrocinnamyl carboxamides at the 6-position. Viable modifications of the 4-amino group were limited and did not allow further optimization of the physical-chemical properties of this class of compounds. Transposition of the 4-amino group to the 2-position of the quinoline core structure provided the 2-aminoquinoline lead class with similar MCH1R binding affinity. A series of 2-aminoquinoline compounds was prepared and evaluated in MCH-1R binding and functional antagonist assays. Small dialkyl, methylalkyl, methylcycloalkyl and cyclic amines along with 3-substituted pyrrolidines were tolerated at the quinoline 2-position. The in vivo efficacy of compound A was explored and compared to that of a related inactive compound B to determine their effects on food intake and body weight in rodents. The biological activities of this matched active – inactive pair provide in vivo proof of concept in rodents that antagonism of MCH1R by a 2-aminoquinoline MCH1R antagonist which led to a reduction of food intake in an acute feeding assay paradigm.
Keywords: Agonist, antagonist, G-protein coupled receptor, Melanin-concentrating hormone, obesity
Current Topics in Medicinal Chemistry
Title: Aminoquinoline Melanin-Concentrating Hormone 1-Receptor (MCH1-R) Antagonists
Volume: 7 Issue: 15
Author(s): Robert J. DeVita
Affiliation:
Keywords: Agonist, antagonist, G-protein coupled receptor, Melanin-concentrating hormone, obesity
Abstract: Structure-activity relationships of a 4-aminoquinoline MCH-1R antagonist lead series were explored by synthesis of analogs with modifications at the 2-, 4- and 6-positions of the original HTS hit. Improvements to the original screening lead were made by addition of lipophilic groups at the 2-position and biphenyl, cyclohexyl phenyl and hydrocinnamyl carboxamides at the 6-position. Viable modifications of the 4-amino group were limited and did not allow further optimization of the physical-chemical properties of this class of compounds. Transposition of the 4-amino group to the 2-position of the quinoline core structure provided the 2-aminoquinoline lead class with similar MCH1R binding affinity. A series of 2-aminoquinoline compounds was prepared and evaluated in MCH-1R binding and functional antagonist assays. Small dialkyl, methylalkyl, methylcycloalkyl and cyclic amines along with 3-substituted pyrrolidines were tolerated at the quinoline 2-position. The in vivo efficacy of compound A was explored and compared to that of a related inactive compound B to determine their effects on food intake and body weight in rodents. The biological activities of this matched active – inactive pair provide in vivo proof of concept in rodents that antagonism of MCH1R by a 2-aminoquinoline MCH1R antagonist which led to a reduction of food intake in an acute feeding assay paradigm.
Export Options
About this article
Cite this article as:
DeVita J. Robert, Aminoquinoline Melanin-Concentrating Hormone 1-Receptor (MCH1-R) Antagonists, Current Topics in Medicinal Chemistry 2007; 7 (15) . https://dx.doi.org/10.2174/156802607782194789
DOI https://dx.doi.org/10.2174/156802607782194789 |
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
-
Meet Our Editorial Board Member:
CNS & Neurological Disorders - Drug Targets Life Cycle of Yeast Prions: Propagation Mediated by Amyloid Fibrils
Protein & Peptide Letters Visuospatial Memory in Healthy Elderly, AD and MCI: A Review
Current Aging Science Drug Targets of Migraine and Neuropathy: Treatment of Hyperexcitability
CNS & Neurological Disorders - Drug Targets The Role of LRRK2 in Neurodegeneration of Parkinson Disease
Current Neuropharmacology New Hope for the Diagnosis and Therapy of Alzheimers Disease
Protein & Peptide Letters Induction of Cellular Oxidative Stress by the β-amyloid Peptide Involved in Alzheimers disease
Protein & Peptide Letters Iodine Impregnated Nano Neutral Alumina as an Efficient Catalyst for One Pot Green Synthesis of Curcumin Analogues by Microwave Irradiation
Letters in Organic Chemistry Gender Related Issues in the Management of Heart Failure
Current Pharmaceutical Design Editorial (Hot Topic:Therapeutic Agents of Lipids and Fatty Acids)
Current Organic Chemistry PON1 Hypermethylation and PON3 Hypomethylation are Associated with Risk of Cerebral Infarction
Current Neurovascular Research Using Mass Spectrometry-Based Peptidomics to understand the Brain and Disorders such as Parkinson’s Disease and Schizophrenia
Current Topics in Medicinal Chemistry Aging in the Perspective of Integrative Medicine, Psychoneuroendocrineimmunology and Hormesis
Current Aging Science Negative Affect and Drinking Drivers: A Review and Conceptual Model Linking Dissonance, Efficacy and Negative Affect to Risk and Motivation for Change
Current Drug Abuse Reviews Effectiveness of Antiretroviral Therapy in HIV-1-Infected Active Drug Users Attended in a Drug Abuse Outpatient Treatment Facility Providing a Multidisciplinary Care Strategy
Current HIV Research β-Catenin Knockdown in Liver Tumor Cells by a Cell Permeable Gamma Guanidine-based Peptide Nucleic Acid
Current Cancer Drug Targets The Role of the New Zealand Intensive Medicines Monitoring Programme in Identification of Previously Unrecognised Signals of Adverse Drug Reactions
Current Drug Safety Patent Selections:
Recent Patents on CNS Drug Discovery (Discontinued) Modulatory Effects of Food Restriction on Brain and Behavioral Effects of Abused Drugs
Current Pharmaceutical Design Th17 Cells: The Role in Immunity
Current Immunology Reviews (Discontinued)