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4‐fluorotranylcypromine, a novel monoamine oxidase inhibitor: Neurochemical effects in rat brain after short‐ and long‐term administration
Author(s) -
Sherry R.L.,
Coutts R.T.,
Baker G.B.
Publication year - 1999
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199910)48:2<61::aid-ddr3>3.0.co;2-o
Subject(s) - tranylcypromine , chemistry , pharmacology , monoamine oxidase , monoamine oxidase inhibitor , serotonin , monoamine neurotransmitter , norepinephrine , reserpine , striatum , in vivo , endocrinology , medicine , dopamine , receptor , biochemistry , biology , enzyme , microbiology and biotechnology
A series of acute and chronic experiments was conducted on 4‐fluorotranylcypromine (FTCP), an analog of the monoamine oxidase (MAO)‐inhibiting antidepressant tranylcypromine (TCP) in which the 4 position of the phenyl ring is protected from metabolism. These studies demonstrated that FTCP is a more potent inhibitor of MAO ex vivo than is the parent drug. Despite its similarity in structure to p‐chloroamphetamine, FTCP does not cause a depletion of brain levels of 5‐hydroxytryptamine (5‐HT) after chronic administration; in fact, it increases brain 5‐HT to levels similar to those produced by TCP. After chronic administration, FTCP produces a downregulation of β‐adrenergic and tryptamine receptors, in common with TCP and several other antidepressants. Pretreatment of rats with iprindole or trifluperazine, drugs known to block cytochrome P450‐mediated hydroxylation reactions and to elevate brain levels of TCP, had no effects on FTCP brain levels, suggesting that metabolic drug–drug interactions may be less of a concern with FTCP than with TCP. In vitro uptake experiments in prisms prepared from hypothalamus or striatum revealed that TCP and FTCP are both potent inhibitors of norepinephrine (NE) uptake; FTCP is a more potent inhibitor of 5‐HT uptake than is TCP. FTCP is a more potent releaser of 5‐HT than is TCP. Drug Dev. Res. 48:61–69, 1999. © 1999 Wiley‐Liss, Inc.