MHP-133, a drug with multiple CNS targets: potential for neuroprotection and enhanced cognition.
MHP-133 is one of a novel series of compounds designed to target multiple brain substrates expected to have synergistic actions in the treatment of cognitive and neurodegenerative disorders such as Alzheimer's disease. The strategy was to develop compounds with multiple targets relevant for enhancing cognition and memory, but avoiding the serious side effects attributed to high potency cholinergic agonists. MHP-133 was shown to interact with subtypes of cholinergic, serotonergic, and imidazoline receptors and to weakly inhibit acetylcholinesterase activity. In vitro, the drug enhanced nerve growth factor (TrkA) receptor expression; it prevented excitotoxicity in a hippocampal slice preparation; and increased the secretion of soluble (non-toxic) amyloid precursor protein. MHP-133 also enhanced cognitive performance by rats and by non-human primate in tasks designed to assess working memory. The results of this study are consistent with the potential use of MHP-133 in the treatment of neurodegenerative disorders such as Alzheimer's disease.
Buccafusco
Jerry J
JJ
Alzheimer's Research Center, Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912, USA. jbuccafu@mcg.edu
Powers
James C
JC
Hernandez
Maria A
MA
Prendergast
Mark A
MA
Terry
Alvin V
AV
Jonnala
Ramamohana R
RR
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002490:Central Nervous System / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D018680:Cholinergic Antagonists / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D018782:Maze Learning; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D016716:PC12 Cells; D011726:Pyridinium Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D018680:Cholinergic Antagonists; C104127:MHP 133; D018696:Neuroprotective Agents; D011726:Pyridinium Compounds; D011956:Receptors, Cell Surface; D020917:Receptor, trkA