Disease relevance of Tetrahydropyridine

• In previous studies, we showed that in the monkey, systemically administered N-methyl, 4-phenyl, 1-2-3-6 tetrahydropyridine (MPTP) produces a chronic parkinsonian syndrome accompanied by spatial frequency-dependent abnormalities in both the pattern electroretinogram and visual evoked potential [1].
• These data are consistent with the concept that the MAO-A-dependent formation of the pyridinium species from the tetrahydropyridine is a prerequisite for toxicity in PC12 cells [2].
• Metabolism of haloperidol and its tetrahydropyridine dehydration product HPTP [3].

High impact information on Tetrahydropyridine

• CEP-1347 (KT7515) promotes neuronal survival at dosages that inhibit activation of the c-Jun amino-terminal kinases (JNKs) in primary embryonic cultures and differentiated PC12 cells after trophic withdrawal and in mice treated with 1-methyl-4-phenyl tetrahydropyridine [4].
• Here we report that short-term oral administration of coenzyme Q induces nigral mitochondrial uncoupling and prevents dopamine cell loss after 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine administration in monkeys [5].
• Probing the active sites of monoamine oxidase A and B with 1,4-disubstituted tetrahydropyridine substrates and inactivators [6].
• SR 57746A (1-[2-(naphth-2-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,5,6- tetrahydropyridine hydrochloride) exhibits neurotrophic activities in vivo and in vitro [7].
• The tetrahydropyridine analog of 10, compound 13, showed a markedly lower receptor affinity (IC50 = 32 +/- 10 microM) and apparently a lower relative efficacy than 10 [8].

Chemical compound and disease context of Tetrahydropyridine

• The neuroleptic agent haloperidol (HP) and its tetrahydropyridine dehydration product HPTP are biotransformed to the potentially neurotoxic HP pyridinium species HPP+ and the reduced HP pyridinium species RHPP+ in humans and rodents [9].

Biological context of Tetrahydropyridine

• [reaction: see text] A regioselective 6-endo reductive cyclization of 2-indolylacyl radicals constitutes the key step of a straightforward synthetic entry to the olivacine skeleton, illustrated by a total synthesis of the tetrahydropyridine alkaloid guatambuine [10].
• These studies support the interpretation that oxidation of MPTP at the C-6 position on the tetrahydropyridine ring is a major rate-determining step in its biotransformation by MAO B [11].
• The findings also suggest a structure/activity relationship of tetrahydropyridine analogs with neurologic and associated neuropathologic manifestations produced in monkeys [12].

Associations of Tetrahydropyridine with other chemical compounds

• Selective azetidine and tetrahydropyridine formation via Pd-catalyzed cyclizations of allene-substituted amines and amino acids [13].
• For the pyridinium and tetrahydropyridine metabolites of haloperidol, there were not marked differences between their potencies as inhibitors between each other for NAT or DAT or between NAT and DAT, with all of the Ki values in the range of 5.8-16 microM [14].
• SR 57746A, 4-(3-trifluoromethylphenyl)-N-[2-(naphth-2-yl)ethyl]-1,2,3,6- tetrahydropyridine HCl, was studied for its specific 5-HT1A receptor agonist action and antidepressant-like effects in the rat [15].
• It appears that conjugation between the tetrahydropyridine ring and a 4-substituent is not a requirement for an MPTP analog to possess neurotoxicity [16].
• Replacement of the tetrahydropyridine ring of PTP by piperidine apparently abolished the ability to act as a substrate for MAO-B [17].

Gene context of Tetrahydropyridine

• 1. The tetrahydropyridine trans-1-methyl-4-[4-dimethylaminophenylethenyl]-1,2,3,6-tetrahydropyridine (t-THP), like MPTP, can undergo monoamine oxidase (MAO)-mediated conversion to a dihydropyridinium intermediate and subsequent metabolism to a pyridinium species. t-THP is also a better substrate for MAO B than MAO A [18].
• The results of these studies provide additional insights into the steric features of the active site of MAO-B and predict that the area in which the C(4) substituent of the tetrahydropyridine ring resides lacks a reactive nucleophilic group [19].
• CEP-1347/KT-7515, an inhibitor of c-jun N-terminal kinase activation, attenuates the 1-methyl-4-phenyl tetrahydropyridine-mediated loss of nigrostriatal dopaminergic neurons In vivo [20].
• Aryl tetrahydropyridine inhibitors of farnesyltransferase: bioavailable analogues with improved cellular potency [21].

References