Biomedical subjects

Leonard T Meltzer

Publications and source records attributed to Leonard T Meltzer.

7 recordsLinked to original sources

PubMed2006

Prevention of dyskinesia by an NMDA receptor antagonist in MPTP monkeys: effect on adenosine A2A receptors.

Adenosine A(2A) receptors (A(2A)R) have received increasing attention for the treatment of L-DOPA-induced dyskinesias in Parkinson disease. In the present study, A(2A)R messenger RNA (mRNA) and receptor-specific binding in the brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys were studied after treatment with L-DOPA and a selective NR1A/2B NMDA receptor antagonist, CI-1041. Four MPTP monkeys received L-DOPA/benserazide and all developed dyskinesias, whereas among the four MPTP monkeys who additionally received CI-1041, only one developed mild dyskinesias. Four normal monkeys and four MPTP-treated monkeys were also studied. All MPTP monkeys had similar striatal dopamine (DA) denervation. A(2A)R mRNA levels, measured by in situ hybridization, were increased in the rostral lateral caudate and putamen of saline-treated MPTP monkeys as well as in the caudal lateral and medial putamen when compared with those of controls. A(2A)R mRNA levels remained elevated in the rostral caudate and putamen of L-DOPA-treated MPTP monkeys when compared with those of controls. A(2A)R mRNA levels of L-DOPA + CI-1041-treated monkeys were at control levels and decreased in the lateral rostral caudate and caudal putamen when compared with those of L-DOPA-treated and saline-treated MPTP monkeys respectively. No change was measured in the caudal medial putamen and caudate nucleus. A(2A)Rs labeled by autoradiography with [(3)H]SCH-58261 had lower level in the L-DOPA + CI-1041-treated MPTP monkeys compared with saline- or L-DOPA-treated MPTP and control monkeys in the rostral lateral and medial caudate and the putamen. No effect of lesion or L-DOPA treatment was measured on [(3)H]SCH-58261-specific binding. These findings suggest that blockade of NMDA receptors could prevent the development of dyskinesias by altering A(2A)Rs.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2006

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.

Animals↗

PubMed2005

Structure-activity relationships of pregabalin and analogues that target the alpha(2)-delta protein.

Pregabalin exhibits robust activity in preclinical assays indicative of potential antiepileptic, anxiolytic, and antihyperalgesic clinical efficacy. It binds with high affinity to the alpha(2)-delta subunit of voltage-gated calcium channels and is a substrate of the system L neutral amino acid transporter. A series of pregabalin analogues were prepared and evaluated for their alpha(2)-delta binding affinity as demonstrated by their ability to inhibit binding of [(3)H]gabapentin to pig brain membranes and for their potency to inhibit the uptake of [(3)H]leucine into CHO cells, a measure of their ability to compete with the endogenous substrate at the system L transporter. Compounds were also assessed in vivo for their ability to promote anxiolytic, analgesic, and anticonvulsant actions. These studies suggest that distinct structure activity relationships exist for alpha(2)-delta binding and system L transport inhibition. However, both interactions appear to play an important role in the in vivo profile of these compounds.

Amines↗

PubMed2004

Subtype selective NMDA receptor antagonists: evaluation of some novel alkynyl analogues.

A benzylpiperidine analogue with an acetylenic linker, 5-(3-[4-(4-fluorobenzyl)-piperidin-1-yl]-prop-1-ynyl)-1,3-dihydrobenzimidazol-2-one (3), was identified as a chemical lead with excellent activity at the NR1A/2B receptor (IC50=3 nM). Efforts to optimize this activity led to focused modifications around the structural motif of 3. The synthesis and SAR studies are discussed.

Alkynes↗

PubMed2003

Orally active analogues of the dopaminergic prodrug 6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one: synthesis and pharmacological activity.

A series of analogues of 6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one (6), an enone prodrug of the mixed DA D(1)/D(2) agonist 5,6-diOH-DPAT (2), was synthesized. The pharmacological profiles of these new enones and their in vivo pharmacological activities were investigated in the Ungerstedt rat rotation model for Parkinson's disease. At 0.1 mg kg(-1) po, the N-methyl-N-n-propyl (12) and the N-ethyl-N-propyl (13) analogues induced pronounced and long lasting pharmacological effects. The pharmacological profile of enone 12 was found to be similar to that of 6, while enone 13 was significantly more potent than 6 (p < 0.01). Analyses of rat brains after the administration of (-)-6 and 13 indicated the presence of hydroxylated metabolites of the parent enones. It is speculated that such metabolites are alpha'-hydroxylated enones that may constitute the first step in the formation of the corresponding catechols.

2-Naphthylamine↗

PubMed2002

A new type of prodrug of catecholamines: an opportunity to improve the treatment of Parkinson's disease.

After decades of research around dopamine agonists, we have found a promising compound in S-PD148903 that represents a new type of prodrug, which in the rat is bioactivated to the catecholamine S-5,6-diOH-DPAT, known to display mixed dopamine D(1)/D(2) receptor agonist properties just like apomorphine. This prodrug has an enone structure which by an oxidative bioactivation mechanism is converted to the corresponding catechol and is delivered enantioselectively into the CNS. This novel concept has the potential to revolutionize the treatment of Parkinson's disease by competing with L-DOPA, the current treatment of choice.

2-Naphthylamine↗

PubMed2002

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.

Animals↗