ABSTRACT
The fact that potent NMDA receptor channel blockers produce phencyclidine-like psychotropic symptoms in man and rodents implies that uncompetitive antagonism of NMDA receptors may not be a promising therapeutic approach. However, recent data indicate that agents with moderate affinity such as memantine and neramexane (MRZ 2/579) are useful therapeutics due to their strong voltage-dependency and rapid unblocking kinetics. Merz has developed a series of novel uncompetitive NMDA receptor antagonists based on an amino-alkylcyclohexane structure. These compounds displaced [(3)H]-MK-801 binding to rat cortical membranes with K(i) values between 1 and 100 microM and inward current responses of cultured hippocampal neurons to NMDA were antagonized in a strongly voltage-dependent manner with rapid blocking/unblocking kinetics. Three of these compounds, with similar biophysical properties to memantine, were chosen for development. MRZ 2/759 (1-ethenyl-3,3,5,5-tetramethyl-cyclohexylamine), 2/1010 (1,3,3,5-tetramethyl-6-azabicyclo[3.2.1]octane) and 2/1013 (8,8,10,10-tetramethyl-1-azaspiro[5.5] undecane) displaced [(3)H]-MK-801 binding with K(i) values of 1.18, 2.59 and 3.64 microM, respectively. They were similarly potent against NMDA-induced currents in hippocampal neurons - IC(50) values of 1.51, 3.06 and 2.20 microM, respectively. In line with their moderate affinity, all were voltage-dependent (delta = 0.86, 0.96 and 0.89, respectively) and fast, open-channel blockers (k(on) 7.90, 1.70 and 2.60 x 10(4) M(-1) sec(-1), k(off) 0.13, 0.12 and 0.24 sec(-1), respectively). These compounds are also NMDA receptor antagonists in the CNS following systemic administration and have good therapeutic indices in a variety of in vivo behavioural models where glutamate is known to play a pivotal role. In view of their relatively low affinity and associated rapid kinetics, they should prove to be useful therapeutics in a wide range of CNS disorders.
Subject(s)
Aza Compounds/pharmacology , Azabicyclo Compounds/pharmacology , Cyclohexylamines/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Neurons/drug effects , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Spiro Compounds/pharmacology , Animals , Binding, Competitive , Cells, Cultured , Cyclopentanes/pharmacokinetics , Dose-Response Relationship, Drug , Hippocampus/drug effects , In Vitro Techniques , Inhibitory Concentration 50 , Memantine/pharmacokinetics , Membrane Potentials/drug effects , Patch-Clamp Techniques , Rats , Receptors, N-Methyl-D-Aspartate/drug effectsABSTRACT
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.
Subject(s)
Cyclohexanes/chemistry , Cyclohexanes/pharmacology , Excitatory Amino Acid Antagonists/chemistry , Excitatory Amino Acid Antagonists/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Clinical Trials as Topic , Cyclohexanes/adverse effects , Cyclohexanes/therapeutic use , Disease Models, Animal , Drug Design , Drug Evaluation, Preclinical , Excitatory Amino Acid Antagonists/adverse effects , Excitatory Amino Acid Antagonists/therapeutic use , Humans , Receptors, N-Methyl-D-Aspartate/metabolism , Structure-Activity RelationshipABSTRACT
A series of 1,3,5-alkylsubstituted cyclohexylamines 2 were synthesized as ligands for the N-methyl-D-aspartate (NMDA) receptor phencyclidine (PCP) binding site. Pure diastereomers with defined configuration of amino group 2-ax and 2-eq were obtained. The optimal size of 1,3,5-substituents was determined for cyclohexylamines 2 with an equatorial amino group in the lowest energy conformation using Hansch analysis. According to the data, the lipophilic part of cyclohexylamines 2 does not discriminate between hydrophobic regions of the PCP binding site but rather recognizes this site as a whole lipophilic pocket.
Subject(s)
Cyclohexylamines/chemical synthesis , Cyclohexylamines/metabolism , Phencyclidine/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Amantadine/chemistry , Amantadine/metabolism , Animals , Binding Sites , Dizocilpine Maleate/chemistry , Dizocilpine Maleate/metabolism , Molecular Mimicry , Rats , Structure-Activity RelationshipABSTRACT
A new method for the preparation of 5beta-cholestan-26-oic acids 7 and their analogs is described. The key steps in the synthesis are: iodination of bis- and tris-formyloxy-5beta-cholan-24-ols 3; nucleophilic substitution of iodides 4 with diethyl sodiomalonate; complete alkaline hydrolysis of esters 5; and subsequent decarboxylation of geminal diacids 6 in DMSO.
