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

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.