Leonard T. Meltzer

mGluR5 metabotropic glutamate receptors and dyskinesias in MPTP monkeys

Modulation of excessive glutamatergic transmission within the basal ganglia is considered as an alternative approach to reduce l-Dopa-induced dyskinesias (LIDs) in Parkinsons disease (PD). In this study receptor binding autoradiography of [3H]MPEP, a metabotropic glutamate receptor 5 (mGluR5) selective radioligand, was used to investigate possible changes in mGluR5 in the basal ganglia of l-Dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys having developed LIDs compared to animals in which LIDs was prevented by adjunct treatments. LIDs were associated with an increase of mGluR5 specific binding in the posterior putamen and pallidum (+41% and +56%) compared to controls. By contrast, prevention of dyskinesias was associated with an important decrease of mGluR5 specific binding in these areas (-37% and -48%) compared with dyskinetic animals. Moreover, an upregulation (+34%) of mGluR5 receptor binding was seen in the anterior caudate nucleus of saline treated MPTP monkeys. This study is the first to provide evidence that enhanced mGluR5 specific binding in the posterior putamen and pallidum may contribute to the pathogenesis of LIDs in PD.

NR2B selective NMDA receptor antagonists.

NR2B antagonists have received considerable attention in recent years. In this class of excitatory amino acid receptor antagonists NR2B antagonists have shown efficacy in neuroprotection, anti-hyperalgesic and anti-Parkinson animal models. Several groups are involved in developing these compounds as therapeutic agents and evaluating newer therapeutic targets for these agents. Until recently benzylpiperidine and phenylpiperidine templates, which were based on the structures of Ifenprodil and Eliprodil, formed the basis of most SAR in this area. A few chemical leads in this class such as CP-101,606, Ro25,6981 and PD0196860 have been identified as possible development leads which have generated significant interest in this area. In addition to the efforts of Pfizer (Parke-Davis), Roche and E.Merck, several other industrial and academic research groups have continued to work in the NR2B area and recently Merck and Roche have reported new chemical leads as NR2B antagonists with significantly different biaryl templates. These new advances have raised hope, for potential success of the NR2B antagonists as new therapeutic agents, for the treatment of several pathophysiological indications.

Prevention of levodopa‐induced dyskinesias by a selective NR1A/2B N‐methyl‐D‐aspartate receptor antagonist in parkinsonian monkeys: Implication of preproenkephalin

Enkephalin is reported to play an important role in the pathophysiology of levodopa (LD) ‐induced dyskinesias. The present study investigated the effect of chronic treatment with a selective NR1A/2B N‐methyl‐D‐aspartate (NMDA) receptor antagonist, CI‐1041, on the expression of preproenkephalin‐A (PPE‐A) in brains of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) ‐treated monkeys in relation to the development of LD‐induced dyskinesias. Four MPTP‐monkeys received LD/benserazide alone; they all developed dyskinesias. Four other MPTP‐monkeys received LD/benserazide plus CI‐1041; only one of them developed mild dyskinesias at the end of the fourth week of treatment. Four normal monkeys and four saline‐treated MPTP monkeys were also included. MPTP‐treated monkeys had extensive and similar striatal dopamine denervation. An increase of PPE‐A mRNA levels assayed by in situ hybridization was observed in the lateral putamen (rostral and caudal) and caudate nucleus (rostral) of saline‐treated MPTP monkeys compared to controls, whereas no change or a small increase was observed in their medial parts. Striatal PPE‐A mRNA levels remained elevated in LD‐treated MPTP monkeys, whereas cotreatment with CI‐1041 brought them back to control values. These findings suggest that chronic blockade of striatal NR1A/2B NMDA receptors with CI‐1041 normalizes PPE‐A mRNA expression and prevents the development of LD‐induced dyskinesias in an animal model of Parkinson disease.

Implication of NMDA Receptors in the Antidyskinetic Activity of Cabergoline, CI-1041, and Ro 61-8048 in MPTP Monkeys with Levodopa-induced Dyskinesias

This study assessed striatal N-methyl-D-aspartate (NMDA) glutamate receptors of 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys with levodopa (L-DOPA)-induced dyskinesias (LID). In a first experiment, four MPTP monkeys receiving L-DOPA/Benserazide alone developed dyskinesias. Four MPTP monkeys received L-DOPA/Benserazide plus CI-1041 an NMDA antagonist selective for NR1/NR2B and four were treated with L-DOPA/Benserazide plus a small dose of cabergoline; one monkey of each group developed mild dyskinesias at the end of treatment. In a second experiment, a kynurenine 3-hydroxylase inhibitor Ro 61-8048, combined with L-DOPA/Benserazide, reduced dyskinesias in MPTP monkeys. Drug-treated MPTP monkeys were compared to intact monkeys and saline-treated MPTP monkeys. Glutamate receptors were investigated by autoradiography using [3H]CGP-39653 (NR1/NR2A antagonist) and [3H]Ro25-6981 (NR1/NR2B antagonist). In general, striatal [3H]CGP-39653 specific binding was unaltered in all experimental groups. MPTP lesion decreased striatal [3H]Ro25-6981 specific binding; these levels were enhanced in the L-DOPA-alone-treated MPTP monkeys and decreased in antidyskinetic drugs treated monkeys. Maximal dyskinesias scores of the MPTP monkeys correlated significantly with [3H]Ro25-6981 specific binding in the rostral and caudal striatum. Hence, MPTP lesion, L-DOPA treatment and prevention of LID with CI-1041 and cabergoline, or reduction with Ro 61-8048 were associated with modulation of NR2B/NMDA glutamate receptors.

Mouse strains differ under a simple schedule of operant learning.

Recent advances in understanding the composition of the human and mouse genomes have paved the way to a more detailed understanding of the influence of genes on behavior, particularly learning and memory. One problem with many learning paradigms is the great length of training time required to generate a stable baseline. Our goal for the current studies was to develop a method of rapidly assessing learning and to use it to compare various strains of mice. The acquisition of a simple nose-poke was determined in operant chambers with two nose-poke holes illuminated: a single nose poke in one hole resulted in the presentation of 0.01 ml evaporated milk; responses in the other hole did not result in dipper presentation. All mice of the B6JxImJ F1, C57BL/6J, 129X1/SvJ and C3H/HeJ mice emitted 50 or more correct operant responses, whereas fewer than 50% of 129X1/SvJ and 75-90% of mice of Balb/cByJ, DBA/2J and the outbred CD-1 mice emitted 50 or more correct operant responses. On average, C57BL/6J emitted 50 operative responses in less than 30 min, whereas DBA/2J mice required nearly 1 h to complete 50 operative responses. Other strains performed at intermediate levels. There was no apparent relationship between operant activity and locomotor activity that may have influenced response acquisition. These findings are consistent with those reported using other learning paradigms and provide a rapid method of learning assessment.

Synthesis and SAR of tolylamine 5-HT6 antagonists

The synthesis and SAR of tolylamines with 5-HT(6) receptor antagonist activity is presented. The amine, core aromatic, peripheral aromatic, and ether linker moieties of HTS hit 1 were modulated and the effect on potency at 5-HT(6) examined. Tolylpiperidine ether 9h was found to possess desirable pharmacokinetic (PK) properties, and was also shown to enhance cognition in the rat novel object recognition paradigm.

Synthesis and in vivo evaluation of 3,4-disubstituted gababutins

A range of 3,4-alkylated five-membered ring derivatives of gabapentin were synthesised. One compound (21) had an excellent level of potency against alpha(2)delta and was profiled in in vivo models of pain and anxiety.