title: Amino-alkyl-cyclohexanes as a novel class of uncompetitive NMDA receptor antagonists.
abstract: Because of its widespread involvement in the physiology and pathology of the CNS, the glutamatergic system has gained considerable attention as a potential target for development of new agents for a number of therapeutic indications. In this respect, the glutamate receptor subtype of the NMDA type has been most intensively studied. The present review describes the rational for developing amino-alkyl-cyclohexanes, as new uncompetitive NMDA receptor antagonists based on our positive experience with memantine which has been used clinically for many years for the treatment of neurodegenerative dementia. Many amino-alkyl-cyclohexane derivatives have been evaluated in vitro and in animal models, and in turn, one structure, namely neramexane HCl (MRZ 2/579) was selected for further development. This agent shows some similarity to memantine e.g. channel blocking kinetics, voltage dependency, and affinity. Preclinical tests indicated particularly good activity in animal models of alcoholism (self-administration, withdrawal-induced audiogenic seizures etc.) and pain (chronic pain, inhibition of tolerance to the analgesic effects of morphine). It turn, this agent has recently entered phase II of clinical trials in alcoholism after a favourable profile seen in phase I studies.
authors.affiliation: Merz+Co, Eckenheimer Landstrasse 100-104, Frankfurt, 60318, Germany. wojciech.danysz@merz.de
authors.forename: W
authors.initials: W
authors.lastname: Danysz
authors.forename: C G
authors.initials: CG
authors.lastname: Parsons
authors.forename: A
authors.initials: A
authors.lastname: Jirgensons
authors.forename: V
authors.initials: V
authors.lastname: Kauss
authors.forename: J
authors.initials: J
authors.lastname: Tillner
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D003510:Cyclohexanes / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D003510:Cyclohexanes; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate