dizocilpine-maleate and (alpha-carboxycyclopropyl)glycine

Glutamate in the basal ganglia has important roles in the regulation of motor processes and this is the first study on the role of inhibitory, group II, metabotropic glutamate receptors (mGluRs) for motor behaviour. The group II agonist (2S,3S,4S)-alpha-carboxycyclopropyl-glycine (L-CCG I) dose dependently induced catalepsy, infused intracerebroventricular (i.c.v.) in rats. The catalepsy was antagonised by dizocilpine and D,L-amphetamine, i.e. by N-methyl-D-aspartate receptor blockade and dopamine receptor activation, respectively. Psychotomimetic side effects limit the clinical use of previously suggested postsynaptic approaches to reduce pathological glutamatergic overactivation, as occuring in epilepsy, ischemia or trauma, but group II agonists provide a new presynaptic approach. Since the catalepsy-induction predicts a lack of psychotomimetic side effects, this study indicates that presynaptic approaches on mGluRs may be more suitable in these situations.

Topics: Amino Acids, Dicarboxylic; Amphetamine; Animals; Catalepsy; Cerebral Ventricles; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Infusions, Parenteral; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley

Using a receptor binding assay for [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-10-imi ne (MK-801) the pharmacology of spinal cord NMDA receptors was compared to that of NMDA receptors in the cerebral cortex. The affinities of glutamate site agonists L-glutamate, L-aspartate, ibotenic acid, NMDA and quinolinic acid for stimulation of [3H]MK-801 binding were 6-10 times lower in the spinal cord and the efficacy of quinolinic acid was 50% of that of the other agonists in this region. Also the affinities of glycine site agonists glycine, D-serine, D-alanine and L-serine were lower in the spinal cord as were the affinities of the non-competitive antagonists phencyclidine, (+/-)-cyclazocine and dextromethorphan. The divalent cations Zn2+, Mg2+ and Ca2+ had 4-8 times lower affinity for spinal NMDA receptors while the affinity of Co2+ was 50 times lower. The affinity of [3H]MK-801 was 2.5-fold lower in the spinal cord. These data show that spinal cord NMDA receptors show qualitative and quantitative differences compared to those in the cerebral cortex.

Topics: Amino Acids, Dicarboxylic; Animals; Binding, Competitive; Cations, Divalent; Cerebral Cortex; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycine; In Vitro Techniques; Male; Protein Binding; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord

The 4 configurational isomers of D-3,4-cyclopropylglutamate (D-CGA) have been synthesized and analyzed for their interactions as excitatory amino acid recognition sites. Additionally, functional assessment of the action of these compounds at the N-methyl-D-aspartate (NMDA) receptor was performed. All 4 analogs function as agonists at the NMDA receptor as evidenced by their ability to stimulate [3H]MK-801 binding to the coupled PCP recognition site. Furthermore, the rank order of potency of these compounds in stimulating [3H]MK-801 binding corresponds with their Ki values for the displacement of NMDA-selective L-[3H]glutamate and [3H]CGS-19755 binding (D-CGA-C greater than D-CGA-B greater than D-CGA-D greater than D-CGA-A). The D-CGA-C isomer has affinity and potency at the NMDA receptor similar to the endogenous agonist, L-glutamate. This high potency coupled with greater specificity than L-glutamate, makes D-CGA-C a potentially useful pharmacological tool for the study of this receptor.

Topics: Amino Acids, Dicarboxylic; Animals; Dibenzocycloheptenes; Dizocilpine Maleate; Male; Rats; Rats, Inbred Strains; Receptors, Amino Acid; Receptors, Cell Surface; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Stereoisomerism