Antagonists at metabotropic glutamate receptor subtype 5: structure activity relationships and therapeutic potential for addiction.
As a result of intensive investigation, particularly in the pharmaceutical industry, a number of potent and selective metabotropic glutamate receptor subtype 5 (mGluR5) antagonists have been discovered. The structure activity relationship studies that led to the discovery of these mGluR5 antagonists are presented in this review. Results from studies on selected mGluR5 antagonists in animal models that simulate drug reward, reinforcement, and relapse appear promising. The comorbidity between drug abuse and anxiety and depression make drugs active in these disorders of great interest. Clinical studies showed that the mGluR5 antagonist fenobam was an active anxiolytic drug. Several new mGluR5 antagonists produced anxiolytic and antidepressant-like effects in animal models of these disorders. The results from the clinical and animal studies provide information for new approaches to finding mechanistically distinct pharmacotherapies to help patients achieve and maintain abstinence from cocaine, methamphetamine, opiates, ethanol, and nicotine (smoking).
Carroll
F Ivy
FI
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC 27709-2194, USA. fic@rti.org
D000437:Alcoholism / Q000188:drug therapy; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001008:Anxiety Disorders / Q000188:drug therapy; D016466:CHO Cells / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003866:Depressive Disorder / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018698:Glutamic Acid / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011487:Protein Conformation; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012907:Smoking / Q000188:drug therapy; D013329:Structure-Activity Relationship; D019966:Substance-Related Disorders / Q000188:drug therapy* / Q000503:physiopathology
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; C578935:GRM5 protein, human; C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid