N-Propynyl analogs of beta-phenylethylidenehydrazines: Synthesis and evaluation of effects on glycine, GABA, and monoamine oxidase

作者：MacKenzie Erin M; Fassihi Afshin; Davood Asghar; Chen Qiao Hong; Rauw Gillian; Rauw Gail; Knaus Edward E; Baker Glen B^*

来源：Bioorganic & Medicinal Chemistry, 2008, 16(17): 8254-8263.

DOI：10.1016/j.bmc.2008.07.027

• gamma-aminobutyric acid (GABA)
• glycine
• monoamine oxidase (MAO)
• N-propynyl analogs of beta-phenylethylidenehydrazine (PEH)

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 ex vivo 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 mu M, and all of the drugs ( including PEH) were poor inhibitors ( at 10 mu M) of MAO-A and -B in vitro. The two analogs studied ex vivo 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.

• 出版日期2008-9-1