Potent Monoamine Oxidase Inhibitors Research Articles

A Simple One-Pot, Three Component Synthesis of 3-Arylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones and their Sulfur Analogues as Potential Monoamine Oxidase Inhibitors

Several new 3-arylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones and 3-aryl-5-oxo-7-thioxo-7,8-dihydropyrimido[4,5-c]pyridazin-5(6H)-ones have been synthesized by a three-component reaction of barbituric acid or thiobarbituric acid with arylglyoxals in the presence of a catalytic amount of pyridine and hydrazine hydrate at room temperature in water.

β-Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO)

Peganum harmala L. is a multipurpose medicinal plant increasingly used for psychoactive recreational purposes (Ayahuasca analog). Harmaline, harmine, harmalol, harmol and tetrahydroharmine were identified and quantified as the main β-carboline alkaloids in P. harmala extracts. Seeds and roots contained the highest levels of alkaloids with low levels in stems and leaves, and absence in flowers. Harmine and harmaline accumulated in dry seeds at 4.3% and 5.6% (w/w), respectively, harmalol at 0.6%, and tetrahydroharmine at 0.1% (w/w). Roots contained harmine and harmol with 2.0% and 1.4% (w/w), respectively. Seed extracts were potent reversible and competitive inhibitors of human monoamine oxidase (MAO-A) with an IC50 of 27μg/l whereas root extracts strongly inhibited MAO-A with an IC50 of 159μg/l. In contrast, they were poor inhibitors of MAO-B. Inhibition of MAO-A by seed extracts was quantitatively attributed to harmaline and harmine whereas inhibition by root extracts came from harmine with no additional interferences. Stems and leaves extracts were poor inhibitors of MAO. The potent inhibition of MAO-A by seed and root extracts of P. harmala containing β-carbolines should contribute to the psychopharmacological and toxicological effects of this plant and could be the basis for its purported antidepressant actions.

Synthesis and molecular modeling of some novel hexahydroindazole derivatives as potent monoamine oxidase inhibitors

A novel series of 2-thiocarbamoyl-2,3,4,5,6,7-hexahydro-1 H-indazole and 2-substituted thiocarbamoyl-3,3a,4,5,6,7-hexahydro-2 H-indazoles derivatives were synthesized and investigated for the ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). The target molecules were identified on the basis of satisfactory analytical and spectra data (IR, 1H NMR, 13C NMR, 2D NMR, DEPT, EI-MASS techniques and elemental analysis). Synthesized compounds showed high activity against both the MAO-A (compounds 1d, 1e, 2c, 2d, 2e) and the MAO-B (compounds 1a, 1b, 1c, 2a, 2b) isoforms. In the discussion of the results, the influence of the structure on the biological activity of the prepared compounds was delineated. It was suggested that non-substituted and N-methyl/ethyl bearing compounds (except 2c) increased the inhibitory effect and selectivity toward MAO-B. The rest of the compounds, carrying N-allyl and N-phenyl, appeared to select the MAO-A isoform. The inhibition profile was found to be competitive and reversible for all compounds. A series of experimentally tested ( 1a– 2e) compounds was docked computationally to the active site of the MAO-A and MAO-B isoenzyme. The autodock 4.01 program was employed to perform automated molecular docking. In order to see the detailed interactions of the docked poses of the model inhibitors compounds 1a, 1d, 1e and 2e were chosen because of their ability to reversibly inhibit the MAO-B and MAO-A and the availability of experimental inhibition data. The differences in the intermolecular hydrophobic and H-bonding of ligands to the active site of each MAO isoform were correlated to their biological data. Observation of the docked positions of these ligands revealed interactions with many residues previously reported to have an effect on the inhibition of the enzyme. Excellent to good correlations between the calculated and experimental K i values were obtained. In the docking of the MAO-A complex, the trans configuration of compound 1e made various very close interactions with the residues lining the active site cavity these interactions were much better than those of the other compounds tested in this study. This tight binding observation may be responsible for the nanomolar inhibition of form of MAOA. However, it binds slightly weaker (experimental K i = 1.23 μM) to MAO-B than to MAO-A (experimental K i = 4.22 nM).

Risk of severe serotonin toxicity following co-administration of methylene blue and serotonin reuptake inhibitors: an update on a case report of post-operative delirium

In a previous case report, published in this journal, we described a postoperative delirium in a patient during recovery from parathyroidectomy. We noted that the delirium resembled serotonin toxicity and that the patient had been taking paroxetine until 2 days before surgery. We offered several tentative explanations for this event, including an adverse interaction between paroxetine and other agent(s) used in the course of the anaesthesia. Recent developments in characterisation of serotonin toxicity have prompted us to re-examine the clinical details surrounding this life-threatening event. It is now known to be important that the patient was given methylene blue, pre-operatively, to enable visualisation of the parathyroid glands. Methylene blue has been found to be a potent inhibitor of monoamine oxidase (MAO), and several cases of serotonin toxicity have been reported recently following its administration. All these cases are consistent with the well-known risk of serotonin toxicity when drugs that augment serotonergic transmission are given in combination with an MAO inhibitor. Methylene blue is used in a variety of surgical settings as well as for treatment of various types of hypotensive shock and methemoglobinaemia. It is also being studied for treatment of Alzheimer's disease and malaria. In this paper, we outline the pharmacology of methylene blue and the aetiology of serotonin toxicity to help prevent further unintentional co-administration of drugs that risk precipitating this life-threatening drug interaction.

Inhibition of monoamine oxidase B by N-methyl-2-phenylmaleimides

Based on a recent report that 1-methyl-3-phenylpyrrolyl analogues are moderately potent reversible inhibitors of the enzyme monoamine oxidase B (MAO-B), a series of structurally related N-methyl-2-phenylmaleimidyl analogues has been prepared and evaluated as inhibitors of MAO-B. In general, the maleimides were more potent competitive inhibitors than the corresponding pyrrolyl analogues. N-Methyl-2-phenylmaleimide was found to be the most potent inhibitor with an enzyme–inhibitor dissociation constant ( K i value) of 3.49 μM, approximately 30-fold more potent than 1-methyl-3-phenylpyrrole ( K i = 118 μM). This difference in activities may be dependent upon the ability of the maleimidyl heterocyclic system to act as a hydrogen bond acceptor. This is in correspondence with literature reports which suggest that hydrogen bond formation is involved in stabilizing inhibitor–MAO-B complexes. Also reported here is a brief kinetic study of the hydrolysis of the N-methyl-2-phenylmaleimidyl analogues in aqueous solution. The findings of the inhibition studies are discussed with reference to the rate and extent of hydrolysis.

Dual inhibition of monoamine oxidase B and antagonism of the adenosine A 2A receptor by ( E, E)-8-(4-phenylbutadien-1-yl)caffeine analogues

The adenosine A 2A receptor has emerged as an attractive target for the treatment of Parkinson’s disease (PD). Evidence suggests that antagonists of the A 2A receptor (A 2A antagonists) may be neuroprotective and may help to alleviate the symptoms of PD. We have reported recently that several members of the ( E)-8-styrylcaffeine class of A 2A antagonists also are potent inhibitors of monoamine oxidase B (MAO-B). Since MAO-B inhibitors are known to possess anti-parkinsonian properties, dual-target-directed drugs that block both MAO-B and A 2A receptors may have enhanced value in the management of PD. In an attempt to explore this concept further we have prepared three additional classes of C-8 substituted caffeinyl analogues. The 8-phenyl- and 8-benzylcaffeinyl analogues exhibited relatively weak MAO-B inhibition potencies while selected ( E, E)-8-(4-phenylbutadien-1-yl)caffeinyl analogues were found to be exceptionally potent reversible MAO-B inhibitors with enzyme–inhibitor dissociation constants ( K i values) ranging from 17 to 149 nM. Furthermore, these ( E, E)-8-(4-phenylbutadien-1-yl)caffeines acted as potent A 2A antagonists with K i values ranging from 59 to 153 nM. We conclude that the ( E, E)-8-(4-phenylbutadien-1-yl)caffeines are a promising candidate class of dual-acting compounds.

Methylene blue is a potent monoamine oxidase inhibitor

Methylene blue is a potent monoamine oxidase inhibitor

Inhibition of monoamine oxidase B by selected benzimidazole and caffeine analogues

We have recently reported that a series of ( E)-8-styrylcaffeines and ( E)-2-styrylbenzimidazoles are moderate to very potent competitive inhibitors of monoamine oxidase B (MAO-B). The most potent member of the series was found to be ( E)-8-(3-chlorostyryl)caffeine (CSC) with an enzyme-inhibitor dissociation constant ( K i value) of 128 nM. In the present study, we have prepared additional caffeine and benzimidazole analogues in an attempt to identify compounds with improved MAO-B inhibition potency while still acting reversibly. The most potent inhibitor among the caffeine analogues was ( E)-8-(3,4-dichlorostyryl)caffeine with a K i value of 36 nM, approximately 3.5 times more potent than CSC. The most potent inhibitor among the benzimidazole analogues was ( E)-2-(4-trifluoromethylstyryl)-1-methylbenzimidazole with a K i value of 430 nM. An SAR analysis indicated that the potency of MAO-B inhibition by ( E)-2-styryl-1-methylbenzimidazole analogues depended upon the Taft steric parameter ( E s) of the substituents attached to C-4 of the styryl phenyl ring. Substituents with a large degree of steric hindrance appear to enhance inhibition potency. The proposal that potent MAO-B inhibition by ( E)-8-styrylcaffeines and ( E)-2-styrylbenzimidazoles can be explained by a mode of binding that involves traversing both the entrance and substrate cavities was supported by the finding that 1-methylbenzimidazole only weakly inhibited MAO-B with a K i value of 2084 μM. Without the styryl side chain, 1-methylbenzimidazole is not expected to be able to bind simultaneously to both the entrance and substrate cavities.

Inhibition of monoamine oxidase B by analogues of the adenosine A 2A receptor antagonist ( E)-8-(3-chlorostyryl)caffeine (CSC)

The adenosine A 2A receptor has emerged as a possible target for the treatment of Parkinson’s disease (PD). Evidence suggests that antagonism of the A 2A receptor not only improves the symptoms of the disease but may also protect against the underlying degenerative processes. We have recently reported that several known adenosine A 2A receptor antagonists (A 2A antagonists) also are moderate to very potent inhibitors of monoamine oxidase B (MAO-B). The most potent among these was ( E)-8-(3-chlorostyryl)caffeine (CSC), a compound frequently used when examining the in vivo pharmacological effects of A 2A antagonists. Since MAO-B inhibitors are also thought to possess antiparkinsonian properties, dual targeting drugs that block both MAO-B and A 2A receptors may have enhanced therapeutic potential in the treatment of PD. In this study, we prepared selected analogues of CSC in an attempt to examine specific structural features that may be important for potent MAO-B inhibition. The results of a SAR study established that the potency of MAO-B inhibition by ( E)-8-styrylcaffeinyl analogues depends upon the van der Waals volume ( V w), lipophilicity ( π), and the Hammett constant ( σ m ) of the substituents attached to C-3 of the phenyl ring of the styryl moiety. Potency also varies with substituents attached to C-4 with bulkiness ( V w) and lipophilicity ( π) being the principal substituent descriptors.

Monoamine Oxidase Inhibition In the Light of New Structural Data

The recent description of the crystal structures of rat MAO-A and human MAO-B provides an unprecedented framework to elucidate the mechanisms underlying the selective interactions between these proteins and their ligands. The analysis of previous and emerging data, in the light of the structural similarities and differences between both isozymes, allows a better understanding of the requirements that determine the affinity and selectivity of substrates and inhibitors. This augurs a new impulse for the rational design of potent and selective MAO inhibitors with therapeutic potential. Keywords: monoamine oxidase, mao inhibitors, structure-activity relationships, crystal structures

Inhibition of MAO A and B by some plant-derived alkaloids, phenols and anthraquinones

A total of seventeen phytochemicals including seven alkaloids (piperine, strychnine, brucine, stachydrine, tetrandrine, frangchinoline and sinomenine), four phenols (paeonol, honokiol, magnolol and eugenol) and six anthraquinones (emodin, rhein, chrysorphanol, aloe-emodin, physcion and 1,8-dihydroxyanthraquinone) was examined for inhibitory activity of monoamine oxidase (MAO) A and B from rat brain mitochondrial. Among these compounds, piperine and paeonol were found to be inhibitory against MAO A in a dose-dependent manner with IC 50 values of 49.3 and 54.6 μM, respectively. Piperine, paeonol and emodin were shown to inhibit MAO B in a dose-dependent manner with the IC 50 data of 91.3, 42.5 and 35.4 μM, respectively. Lineweaver–Burk transformation of the inhibition data indicated that the inhibitory action of piperine on MAO A was of mixed type, and that of paeonol on the same type of the enzyme was of non-competitive type. For piperine, the K i and K I were determined to be 35.8 and 25.7 μM, respectively. For paeonol, the K i was estimated to be 51.1 μM. The inhibition of piperine and paeonol on MAO B was of competitive type with K i values of 79.9 and 38.2 μM, respectively. The inhibition of emodin on MAO B was of mixed type with the K i and K I data of 15.1 and 22.9 μM, respectively. The present investigation showed that the phytochemicals piperine, paeonol and emodin are potent MAO inhibitors whereas other compounds were inactive against any type of MAO at 100 μM in the present assay.

Rasagiline: an anti-Parkinson drug with neuroprotective activity

Mitochondria are now recognized as potent integrators and co-ordinators of cellsurvival/death and apoptosis. Therefore, they are pharmacological targets for induction or correction of excessive cell death in human pathology, which includes cancer and the neurodegenerative disorders Parkinson’s and Alzheimer’s disease. One such agent is the anti-Parkinson drug, rasagiline, a novel neuroprotective–antiapoptotic second-generation potent irreversible selective inhibitor of monoamine oxidase B. It prevents theneurotoxin-initiated demise of mitochondria via modulation of cell survival/death Bcl-2 family proteins, Bcl-2–Bax, at the mitochondria permeability transition pore, which regulates voltage-dependent anion channels. It may also induce long-term potentiation– a consequence of its protein kinase C-dependent mitogen-activated protein kinase pathway activation. Rasagiline, unlike selegiline, is devoid of sympathomimetic action and is not metabolized to neurotoxic methamphetamine, but to aminoindan. Its neuroprotective activity is attributed to the aminoindan and propargylamine moieties and structural resemblance to certain metabotrophic glutamate 1 receptor antagonists. Ragagiline has been chosen for neuroprotective studies by the National Institutes of Health as a possible disease-modifying agent.

Synthesis of daidzin analogues as potential agents for alcohol abuse

Daidzin, the active principle of an herbal remedy for ‘alcohol addiction’, has been shown to reduce alcohol consumption in all laboratory animals tested to date. Correlation studies using structural analogues of daidzin suggests that it acts by raising the monoamine oxidase (MAO)/mitochondrial aldehyde dehydrogenase (ALDH-2) activity ratio ( J. Med. Chem. 2000, 43, 4169). Structure–activity relationship (SAR) studies on the 7- O-substituted analogues of daidzin have revealed structural features important for ALDH-2 and MAO inhibition ( J. Med. Chem. 2001, 44, 3320). We here evaluated effects of substitutions at 2, 5, 6, 8, 3′ and 4′ positions of daidzin on its potencies for ALDH-2 and MAO inhibition. Results show that analogues with 4′-substituents that are small, polar and with hydrogen bonding capacities are most potent ALDH-2 inhibitors, whereas those that are non-polar and with electron withdrawing capacities are potent MAO inhibitors. Analogues with a 5-OH group are less potent ALDH-2 inhibitors but are more potent MAO inhibitors. All the 2-, 6-, 8- and 3′-substituted analogues tested so far do not inhibit ALDH-2 and/or have decreased potencies for MAO inhibition. This, together with the results obtained from previous studies, suggests that a potent antidipsotropic analogue would be a 4′,7-disubstituted isoflavone. The 4′-substituent should be small, polar, and with hydrogen bonding capacities such as, –OH and –NH 2; whereas the 7-substituent should be a straight-chain alkyl with a terminal polar function such as –(CH 2) n –OH with 2≤ n ≤6, –(CH 2) n –COOH with 5≤ n ≤10, or –(CH 2) n –NH 2 with n ≥4.

Inhibition of Amine Oxidases Activity by 1‐Acetyl‐3,5‐diphenyl‐4,5‐dihydro‐(1H)‐pyrazole Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Inhibition of amine oxidases activity by 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives

A novel series of 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives have been synthesised and investigated for the ability to inhibit selectively monoamine oxidases, swine kidney oxidase, and bovine serum amine oxidase. The newly synthesised compounds 1– 6 proved to be reversible and non-competitive inhibitors of all types of the assayed amine oxidases. Compounds inhibit monoamine oxidases potently, displaying low I 50 values of particular interest. In particular 1-acetyl-3-(2,4-dihydroxyphenyl)-5-(3-methylphenyl)-4,5-dihydro-(1H)-pyrazole 6 showed to be a potent monoamine oxidase inhibitor with a K i of about 10 −8 M. Further insights in the theoretical evaluation of the possible interactions between the compounds and monoamine oxidase B have been developed through a computational approach.

Side-chain metabolism of propranolol: involvement of monoamine oxidase and aldehyde reductase in the metabolism of N-desisopropylpropranolol to propranolol glycol in rat liver

The further metabolism of N-desisopropylpropranolol (NDP), a side-chain metabolite of propranolol (PL), was investigated in isolated rat hepatocytes. Propranolol glycol (PGL) was generated from NDP as a major metabolite. Naphtetrazole (NTE), a potent inhibitor of monoamine oxidase (MAO), significantly retarded the disappearance of NDP from the incubation medium, suggesting the involvement of MAO in the deamination of NDP to an aldehyde intermediate. In a reaction mixture of rat liver mitochondria and cytosol with NADPH, phenobarbital, a specific inhibitor of aldehyde reductase, and 4-nitrobenzaldehyde (4-NBA), a substrate inhibitor of aldehyde reductase, decreased the formation of PGL from NDP. 4-NBA was a competitive inhibitor of the enzyme responsible for the PGL formation. The optimal pH for the formation of PGL from NDP in the reaction mixture was approximately 8.0. Based on these results, we propose the possibility that, in the rat liver, MAO catalyzes the oxidative deamination of NDP to an aldehyde intermediate and the formed aldehyde intermediate is subsequently reduced to PGL by aldehyde reductase. Furthermore, the enantioselective metabolism of NDP to PGL was examined. In isolated rat hepatocytes, the amount of PGL formed from S-NDP [ S(−)-form of NDP] was larger than that of PGL formed from R-NDP [ R(+)-form of NDP].

Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B.

1. Rasagiline [N-propargyl-1R(+)-aminoindan], was examined for its monoamine oxidase (MAO) A and B inhibitor activities in rats together with its S(-)-enantiomer (TVP 1022) and the racemic compound (AGN-1135) and compared to selegiline (1-deprenyl). The tissues that were studied for MAO inhibition were the brain, liver and small intestine. 2. While rasagiline and AGN1135 are highly potent selective irreversible inhibitors of MAO in vitro and in vivo, the S(-) enantiomer is relatively inactive in the tissues examined. 3. The in vitro IC(50) values for inhibition of rat brain MAO activity by rasagiline are 4.43+/-0.92 nM (type B), and 412+/-123 nM (type A). The ED(50) values for ex vivo inhibition of MAO in the brain and liver by a single dose of rasagiline are 0.1+/-0.01, 0.042+/-0.0045 mg kg(-1) respectively for MAO-B, and 6.48+/-0.81, 2.38+/-0.35 mg kg(-1) respectively for MAO-A. 4. Selective MAO-B inhibition in the liver and brain was maintained on chronic (21 days) oral dosage with ED(50) values of 0.014+/-0.002 and 0.013+/-0.001 mg kg(-1) respectively. 5. The degree of selectivity of rasagiline for inhibition of MAO-B as opposed to MAO-A was similar to that of selegiline. Rasagiline was three to 15 times more potent than selegiline for inhibition of MAO-B in rat brain and liver in vivo on acute and chronic administration, but had similar potency in vitro. 6. These data together with lack of tyramine sympathomimetic potentiation by rasagiline, at selective MAO-B inhibitory dosage, indicate that this inhibitor like selegiline may be a useful agent in the treatment of Parkinson's disease in either symptomatic or L-DOPA adjunct therapy, but lack of amphetamine-like metabolites could present a therapeutic advantage for rasagiline.

Antioxidant activity of the monoamine oxidase B inhibitor lazabemide

Free radical-induced damage to lipid and protein constituents of neuronal membranes contributes to the pathophysiology of neurodegenerative diseases, including Alzheimer’s disease (AD). The development of an effective inhibitor of oxidative stress represents an important goal for the treatment of AD. In this study, the intrinsic antioxidant activity of lazabemide, a potent and reversible inhibitor of monoamine oxidase B (MAO-B), was tested in a membrane-based model of oxidative stress. Under physiologic-like conditions, lazabemide inhibited lipid peroxidation in a highly concentration-dependent manner. At low, pharmacologic levels of lazabemide (100.0 nM), there was a significant ( P < 0.001) and catalytic reduction in lipid peroxide formation, as compared with control samples. The antioxidant activity of lazabemide was significantly more effective than that of either vitamin E or the MAO-B inhibitor, selegiline. The ability of lazabemide to inhibit oxidative damage is attributed to physico-chemical interactions with the membrane lipid bilayer, as determined by small angle x-ray diffraction methods. By partitioning into the membrane hydrocarbon core, lazabemide can inhibit the propagation of free radicals by electron-donating and resonance-stabilization mechanisms. These findings indicate that lazabemide is a potent and concentration-dependent inhibitor of membrane oxy-radical damage as a result of inhibiting membrane lipid peroxidation, independent of MAO-B interactions.

Rasagiline, a novel monoamine oxidase-B inhibitor with neuroprotective effects under ischemic conditions in PC12 cells

Rasagiline (N-propargyl-1R-aminoindan) is a novel, potent, selective, and irreversible inhibitor of monoamine oxidase B (MAO-B), currently in Phase III trials for the treatment of Parkinson disease (PD). Rasagiline was shown to have neuroprotective properties in various in vitro and in vivo models independently of MAO-B inhibition. Recently, we developed an in vitro oxygen-glucose deprivation (OGD) model of time-course dependent neuronal cell death in nerve growth factor (NGF)-differentiated PC12 cultures. OGD was accompanied by activation of the arachidonic acid cascade and a decrease in ATP content, changes typical of ischemic conditions. OGD for 3 h followed by reoxygenation for 18 h caused about 30–40% cell death. These conditions are suitable for testing the effect of potential neuroprotective compounds on neuronal cell death. Rasagiline markedly reduced OGD-induced cell death independently of MAO-B inhibition, reducing OGD-induced cell death even when added after the OGD insult. The compound also inhibited OGD-induced prostaglandin E2 (PGE2) release in a dose-dependent manner. At present, selegiline remains the only drug approved for PD therapy based on MAO-B inhibition. However, in contrast to selegiline, rasagiline is not metabolized to amphetamine-like products, which cause adverse side effects and neuronal cell death. Therefore, rasagiline, whose neuroprotective properties are uncomplicated by the production of neurotoxic metabolites, may have an advantage over selegiline in the treatment of PD. Drug Dev. Res. 50:285–290, 2000. © 2000 Wiley-Liss, Inc.

4-fluorotranylcypromine, a novel monoamine oxidase inhibitor: Neurochemical effects in rat brain after short- and long-term administration

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.