A novel class of amino-alkylcyclohexanes as uncompetitive, fast, voltage-dependent, N-methyl-D-aspartate (NMDA) receptor antagonists – in vitro characterization (original) (raw)

2007, Journal of Neural Transmission

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 mM 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 (1ethenyl-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 mM, respectively. They were similarly potent against NMDA-induced currents in hippocampal neurons -IC 50 values of 1.51, 3.06 and 2.20 mM, respectively. In line with their moderate affinity, all were voltage-dependent (d ¼ 0.86, 0.96 and 0.89, respectively) and fast, open-channel blockers (k on 7.90, 1.70 and 2.60 Â 10 4 M À1 sec À1 , k off 0.13, 0.12 and 0.24 sec À1 , 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.