Abstract
Non-selective cannabinoid ligands display a wide range of physiological effects including analgesic, antiinflammatory, anti-convulsive and immuno-suppressive activities. A separation between therapeutic effects and undesirable CNS side effects may be accomplished by increasing the selectivity for the CB2 receptor over the CB1 receptor. There is considerable interest in developing new cannabimimetic compounds possessing preferentially high affinity for the CB2 receptor as potential novel therapeutics for the treatment of inflammation and chronic pain. This review will summarize the literature on selective cannabinoid CB2 receptor agonists from 2007 to the present, with special emphasis on SAR and medicinal chemistry strategies to improve physicochemical properties, metabolic stability and oral bioavailabilty of these inherently lipophilic ligands. Incorporating physicochemical property filters early in hit identification, concurrent screening of liver microsomal stability and addressing metabolic hot-spots through structural modifications or bio-isosteric replacements during lead optimization led to a number of structurally diverse CB2 agonists with good oral bioavailability and in vivo efficacy in rodent models of pain.
Current Pharmaceutical Design
Title: Simultaneous Optimization of Potency, Selectivity and Physicochemical Properties for Cannabinoid CB2 Ligands
Volume: 15 Issue: 29
Author(s): Karin Worm and Roland E. Dolle
Affiliation:
Abstract: Non-selective cannabinoid ligands display a wide range of physiological effects including analgesic, antiinflammatory, anti-convulsive and immuno-suppressive activities. A separation between therapeutic effects and undesirable CNS side effects may be accomplished by increasing the selectivity for the CB2 receptor over the CB1 receptor. There is considerable interest in developing new cannabimimetic compounds possessing preferentially high affinity for the CB2 receptor as potential novel therapeutics for the treatment of inflammation and chronic pain. This review will summarize the literature on selective cannabinoid CB2 receptor agonists from 2007 to the present, with special emphasis on SAR and medicinal chemistry strategies to improve physicochemical properties, metabolic stability and oral bioavailabilty of these inherently lipophilic ligands. Incorporating physicochemical property filters early in hit identification, concurrent screening of liver microsomal stability and addressing metabolic hot-spots through structural modifications or bio-isosteric replacements during lead optimization led to a number of structurally diverse CB2 agonists with good oral bioavailability and in vivo efficacy in rodent models of pain.
Export Options
About this article
Cite this article as:
Worm Karin and Dolle E. Roland, Simultaneous Optimization of Potency, Selectivity and Physicochemical Properties for Cannabinoid CB2 Ligands, Current Pharmaceutical Design 2009; 15 (29) . https://dx.doi.org/10.2174/138161209789105027
DOI https://dx.doi.org/10.2174/138161209789105027 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...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
-
Thyroid Hormone Antagonists: Potential Medical Applications and Structure Activity Relationships
Current Medicinal Chemistry Artificial Intelligence in Pharmaceutical Field - A Critical Review
Current Drug Delivery Rational Design of Antimalarial Drugs Using Molecular Modeling and Statistical Analysis
Current Pharmaceutical Design Progress in the Developement of Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2
Current Medicinal Chemistry Anti-Hypertensive Potential and Epigenetics of Angiotensin II type 2 Receptor (AT2R)
Current Hypertension Reviews TTR Fibril Formation Inhibitors: Is there a SAR?
Current Medicinal Chemistry Inhaled Corticosteroids and Pneumonia in Chronic Obstructive Pulmonary Disease
Current Respiratory Medicine Reviews New Antitumour Natural Products from Marine Red Algae: Covering the Period from 2003 to 2012
Mini-Reviews in Medicinal Chemistry New Cathepsin D Inhibitor Library Utilizing Hydroxyethyl Isosteres with Cyclic Tertiary Amines
Medicinal Chemistry Touting Traditional Knowledge and Herbal Medicine to Combat and Prevent COVID-19
Current Pharmaceutical Biotechnology Repurposing of Chemotherapeutics to Combat COVID-19
Current Topics in Medicinal Chemistry Development of New Therapeutic Agents for Fibrodysplasia Ossificans Progressiva.
Current Molecular Medicine Benzenecarboxamide Analogs of Fluoroquinolones (BCFQs). Antibacterial Activity and SAR Studies
Letters in Drug Design & Discovery Salen Mn Complexes Mitigate Radiation Injury in Normal Tissues
Anti-Cancer Agents in Medicinal Chemistry The Biological and Clinical Activity of Anti-Malarial Drugs In Autoimmune Disorders
Current Rheumatology Reviews Synthesis of 1,3,6-Trioxygenated Prenylated Xanthone Derivatives as Potential Antitumor Agents
Letters in Organic Chemistry Potential Neuroprotective Effect of Cannabinoids in COVID-19 Patients
Current Topics in Medicinal Chemistry Quercetin and its Relative Therapeutic Potential Against COVID-19: A Retrospective Review and Prospective Overview
Current Molecular Medicine Targeting Virus-Induced Reprogrammed Cell Metabolism <i>via</i> Glycolytic Inhibitors: An Effective Therapeutic Approach Against SARS-CoV-2
Mini-Reviews in Medicinal Chemistry Progress in the Preparation and Testing of Glycine Transporter Type-1 (GlyT1) Inhibitors
Current Topics in Medicinal Chemistry