The involvement of glutamatergic transmission in the mechanism of movement disorders induced by reversive rotation of white mice.

The ability of the selective non-competitive NMDA receptor blocker MK-801 and a series of new glutamate antagonists --the adamantane derivatives IEM-1754 and IEM-1857 and phencyclidine (IEM-1925)--to prevent movement disorders induced by reversive rotation in mice was studied. l.p. MK-801 at a dose of 0.15 ml and IEM-1754 at a dose of 5.0 mg/kg prevented the development of akinesia in response to reversive rotation as effectively as scopolamine, a known agent which provides effective prophylaxis for movement diseases. IEM-1857, the quaternary analog of IEM-1754, was not effective. IEM-1925 significantly increased the responses of mice to reversive rotation, possibly because of its high activity in relation to other subtypes of glutamate receptors. These data provide evidence for the involvement of glutamatergic transmission in the mechanism of movement disorders of vestibular origin.

Study of cholinoreceptive membrane in sympathetic ganglion by analysis of structure-activity relationship.

Asymmetrical analogs of bistrimethylammonium salts were synthesized which had 4-6 methylene groups, one trimethylammonium cationic head and another cationic head which could be systematically altered. They were tested for their ganglion-blocking activity on the cat superior cervical sympathetic ganglion. These asymmetrical analogs were substantially more active than symmetrical ones. This fact favors the hypothesis that the two anionic sites on the cholinoreceptor surface with which bis-cation gangliolytics combined are not identical. One of these sites is assumed to be the main anionic site of the cholinoreceptor which is geometrically complementary to the trimethylammonium group of acetylcholine; the second anionic site, which is not structurally identical with the main anionic site of the cholinoreceptor, is located at a distance of 4 methylene groups. Not only the different geometry of the cationic head but hydrophobic interactions and hydrogen bonding seem to be very important for optimal binding to the second anionic site and thereby for high ganglion-blocking activity. The possible role of the second anionic site in receptor function is discussed.

Novel adamantane derivatives act as blockers of open ligand-gated channels and as anticonvulsants.

We examined the influence of the molecular structure of four novel adamantane derivatives on their ability to block the channels of nicotinic acetylcholine (ACh) and N-methyl-D-aspartate (NMDA) receptors. The structure of the drugs is Ad-CH2-N+H2-(CH2)5-R, where Ad is adamantane and R was varied from ammonium (IEM-1754) to tert-butyldimethylammonium (IEM-1857) radical. The compounds induced double-exponential decays of postsynaptic currents in frog muscles and flickering of NMDA-activated channels, suggesting that each drug acts as a fast open-channel blocker at both types of receptors. The equilibrium dissociation constants (Kd) of the drugs for ACh-activated channels at -80 mV were similar, whereas the Kd values for NMDA-activated channels at -80 mV were 2-10 times lower. Several observations suggested that occupation of either type of channel by these compounds inhibited channel closure; the time constant (tau) of the slow component of the decay of postsynaptic currents in the presence of each compound was greater than the control tau, the IC50 of IEM-1754 for inhibition of NMDA-activated whole-cell currents was > 20 times larger than its Kd for the open channel, and a transient increase in NMDA-activated whole-cell currents was observed after washout of IEM-1754. Thus, these drugs appear to act on nicotinic ACh and NMDA receptors via similar mechanisms, although the voltage dependence of block suggested that the drugs bind at a more superficial site in the ACh-activated channel. All compounds also potently prevented NMDA-induced convulsions in mice. The ED50 of IEM-1754 was 4 times lower than the ED50 of MK-801.

Architecture of the neuronal nicotinic acetylcholine receptor ion channel at the binding site of bis-ammonium blockers.

Structure-activity relationships of 56 pentamethylenbis-ammonium compounds, the blockers of the neuronal nicotinic acetylcholine receptor (nAChR) ion channel, have been studied to estimate the cross-sectional dimensions of the channel pore. The cat superior cervical sympathetic ganglion in situ and isolated guinea pig ileum were used to evaluate the potency of the compounds to block ganglionic transmission. Minimum-energy conformations of each compound were calculated by the molecular mechanics method. A topographic model of the binding site of the blockers was proposed. It incorporates two narrowings, a large and a small one. The small narrowing is located between the large one and the cytoplasmic end of the pore. The cross-sectional dimensions of the large and small narrowings estimated from the dimensions of the blockers are 6.1 x 8.3 A and 5.5 x 6.4 A, respectively, the distance between the narrowings along the pore being approximately 7 A. Most potent blockers would occlude the pore via binding to the channel at the levels of both narrowings. Less potent blockers are either too large or too small to bind to both narrowings simultaneously: large blockers would occlude the pore at the level of large narrowing, while small blockers would pass the large narrowing and occlude the pore at the level of small narrowing only. A comparison of the topographic model with a molecular five-helix bundle model of nAChR pore predicts Serine and Threonine rings to be the most probable candidates for the large and small narrowings, respectively.