title: N-Propynyl analogs of beta-phenylethylidenehydrazines: synthesis and evaluation of effects on glycine, GABA, and monoamine oxidase.
abstract: A group of beta-phenylethylidenehydrazines possessing a variety of substituents (Me, OMe, Cl, F, and CF(3)) at the ortho-, meta-, or para-positions of the phenyl ring, in conjunction with either a N-bis-(2-propynyl) or a N-mono-(2-propynyl) moiety, were synthesized and compared to the novel neuroprotective drug beta-phenylethylidenehydrazine (PEH) with regard to their ability to inhibit the enzymes GABA-transaminase (GABA-T) and monoamine oxidase (MAO)-A and -B in vitro in brain tissue. Two of the analogs synthesized (mono- and bis-N-propynylPEH) were also studied exvivo in rats to compare their effects to those of PEH with regard to ability to inhibit GABA-T and MAO and to change brain levels of several important amino acids. Unlike PEH, none of the new drugs inhibited GABA-T in vitro at 10 or 100 microM, and all of the drugs (including PEH) were poor inhibitors (at 10 microM) of MAO-A and -B invitro. The two analogs studied exvivo inhibited GABA-T to a lesser extent than PEH, unlike PEH that did not elevate brain levels of GABA, and inhibited MAO-A and -B more potently than PEH. Interestingly, unlike PEH, the two analogs caused marked increases in brain levels of glycine; because of the current interest in drugs that increase glycine availability in the brain as potential antipsychotic drugs, these two analogs now warrant further investigation.
authors.affiliation: Neurochemical Research Unit and Bebensee Schizophrenia Research Unit, Department of Psychiatry, University of Alberta, 12-105B Clinical Sciences Building, Edmonton, Alta., Canada T6G 2G3.
authors.forename: Erin M
authors.initials: EM
authors.lastname: MacKenzie
authors.forename: Afshin
authors.initials: A
authors.lastname: Fassihi
authors.forename: Asghar
authors.initials: A
authors.lastname: Davood
authors.forename: Qiao-Hong
authors.initials: QH
authors.lastname: Chen
authors.forename: Gillian
authors.initials: G
authors.lastname: Rauw
authors.forename: Gail
authors.initials: G
authors.lastname: Rauw
authors.forename: Edward E
authors.initials: EE
authors.lastname: Knaus
authors.forename: Glen B
authors.initials: GB
authors.lastname: Baker
mesh_terms: D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors*; D000480:Alkynes / Q000737:chemistry*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005998:Glycine / Q000378:metabolism; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000480:Alkynes; D004791:Enzyme Inhibitors; D006834:Hydrazines; C022030:methylacetylene; D008995:Monoamine Oxidase; D000612:4-Aminobutyrate Transaminase; D005998:Glycine