Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chemical modification of PLG, comprising replacement of proline or/and leucine by unnatural amino acids led to analogs with high oral efficacy. The most active analog identified in the course of our works was 1-prolyl-2-phenyl-1-2-aminobutanoylglycinamide (Doreptide). Doreptide is presently further evaluated as a new drug for the treatment of Parkinson's disease.
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PMID:L-dopa potentiating analogs of Pro-Leu-Gly-NH2 with oral efficacy. 167 11

1. In view of previously demonstrated modulatory effects of PLG on the sensitivity of central dopamine receptors, we developed a radioligand binding assay to identify specific binding sites of PLG in rat and normal human brain. 2. 3H-PLG binds specifically to rat striatum exhibiting high affinity (KD = 4.69 +/- 0.50 nM) saturability (Bmax = 9.20 +/- 0.30 fmoles/mg protein) and reversibility; the highest density of specific PLG binding sites occurring in the striatum, followed by the hypothalamus and cerebral cortex. 3. Saturable, high-affinity binding sites of PLG were identified in human striatum. The substantia nigra was enriched with the highest level of specific PLG binding sites. 4. Dopamine receptors were identified in human lymphocytes. 5. The results are compatible with the hypothesis that differential modulation of CNS dopamine receptors by PLG is functionally associated with interacting with specific PLG binding sites in the rat and human brain, and pose implications for Parkinson's disease and tardive dyskinesia.
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PMID:CNS putative L-prolyl-L-leucyl-glycinamide (PLG) receptors, brain and lymphocyte dopamine receptors. 629 84

The diketopiperazine "C5" conformational mimic has been incorporated into the L-prolyl-L-leucylglycinamide (PLG, 1) structure and into the bicyclic lactam PLG peptidomimetic structure 3 to give compounds 5 and 6, respectively. These analogues were designed to explore the idea that the N-terminal "C5" conformation, which was found in the crystal structure of 2 and which was mimicked in 4 by the diketopiperazine function, was a factor in the high potency of these two agents. Through the use of the [3H]spiroperidol/N-propylnorapomorphine (NPA) D2 receptor competitive binding assay, both 5 and 6 were found to increase the affinity of the dopamine receptor for agonists and both were found to increase the percentage of D2 receptors which existed in the high-affinity state. These effects were observed when Gpp(NH)p was either absent or present, and they were analogous to the effects observed previously for PLG and the PLG peptidomimetics 2 and 4. However, the potency seen with 5 and 6 was less than that seen for 2 and 4, suggesting that while the N-terminal "C5" conformation may play a role in the potency of the gamma-lactam peptidomimetics of PLG, it does not appear to be the primary factor. In the 6-hydroxydopamine-lesioned animal model of Parkinson's disease, 5 altered apomorphine-induced rotational behavior in a dose-dependent manner. The maximum effect occurred at a dose of 0.01 mg/kg i.p. and resulted in a 52.27 +/- 13.96% (p < 0.001, n = 7) increase in rotations compared to apomorphine administered alone.
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PMID:Design, synthesis, and dopamine receptor modulating activity of diketopiperazine peptidomimetics of L-prolyl-L-leucylglycinamide. 935 26

Central dopaminergic systems are implicated in schizophrenia and Parkinson's disease, and are known to be modulated by the endogenous tripeptide Pro-Leu-Gly-NH(2) (PLG or MIF-1, melanocyte-stimulating hormone release inhibiting factor-1). Differential display polymerase chain reaction (ddPCR) was utilized to identify genes that are regulated by protracted PLG treatment (20 mg/kg, i.p. for 28 days) in male Sprague-Dawley rats. A total of 2400 genes were screened and 3 down-regulated bands were identified in the PLG-treated samples. Sequencing analysis revealed a total of six unique cDNA species. One fragment possessed a high degree of homology with Mus musculus hnRNP-L (protein L) mRNA (GenBank #AB009392) (termed PRG1: PLG regulated gene 1). Elongation of the PRG1 cDNA, by RACE-PCR, provided an 835 bp sequence with 95% homology to AB009392 over a 743 bp span. Open reading frame analysis provided a putative amino acid sequence consistent with the identity of PRG1 as rat hnRNP-L. Northern hybridization experiments with PRG1 revealed a 2.3 kb mRNA species that was decreased by 65% in the PLG-treated tissue. Western blot analysis revealed significantly decreased hnRNP-L levels in the striatum and pre-frontal cortex (but not the nucleus accumbens) by 71 and 61%, respectively of PLG-treated animals. The identification of altered expression of hnRNP-L following PLG treatment provides insight into the long-term effects of PLG and may provide insight into its molecular mechanism of action.
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PMID:PLG regulates hnRNP-L expression in the rat striatum and pre-frontal cortex: identification by ddPCR. 1257 95