High-throughput virtual screening and quantum mechanics approach to develop imipramine analogues as leads against trypanothione reductase of leishmania.

Visceral leishmaniasis (VL) has been considered as one of the most fatal form of leishmaniasis which affects 70 countries worldwide. Increased drug resistance in Indian subcontinent urged the need of new antileishmanial compounds with high efficacy and negligible toxicity. Imipramine compounds have shown impressive antileishmanial activity. To find out most potent analogue from imipramine series and explore the inhibitory activity of imipramine, we docked imipramine analogues (n=93,328) against trypanothione reductase in three sequential modes. Furthermore, 98 ligands having better docking score than reference ligand were subjected to ADME and toxicity, binding energy calculation and docking validation. Finally, Molecular dynamic and single point energy was estimated for best two ligands. This study uncovers the inhibitory activity of imipramine against Leishmania parasites.

Synthesis and inhibitory evaluation of 3-linked imipramines for the exploration of the S2 site of the human serotonin transporter.

The human serotonin transporter is the primary target of several antidepressant drugs, and the importance of a primary, high affinity binding site (S1) for antidepressant binding is well documented. The existence of a lower affinity, secondary binding site (S2) has, however, been debated. Herein we report the synthesis of 3-position coupled imipramine ligands from clomipramine using a copper free Sonogashira reaction. Ligand design was inspired by results from docking and steered molecular dynamics simulations, and the ligands were utilized in a structure-activity relationship study of the positional relationship between the S1 and S2 sites. The computer simulations suggested that the S2 site does indeed exist although with lower affinity for imipramine than observed within the S1 site. Additionally, it was possible to dock the 3-linked imipramine analogs into positions which occupy the S1 and the S2 site simultaneously. The structure activity relationship study showed that the shortest ligands were the most potent, and mutations enlarging the proposed S2 site were found to affect the larger ligands positively, while the smaller ligands were mostly unaffected.

N-demethylation and N-oxidation of imipramine in rat thoracic aortic endothelial cells.

The aim of this study was to examine whether cultured rat thoracic aortic endothelial cells (TAECs) have the ability to metabolize the tertiary amine, imipramine. In rat TAECs, imipramine was biotransformed into N-demethylate and N-oxide by cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO), respectively. The intrinsic clearance (V max/K m) for the N-oxide formation was approximately five times as high as that for the N-demethylate formation, indicating that oxidation by CYP was much higher than that by FMO. Moreover, we suggest that CYP2C11 and CYP3A2 are key players in the metabolism to N-demethylate in rat TAECs using the respective anti-rat CYP antibodies (anti-CYP2C11 and anti-CYP3A2). The presence of CYP2C11 and CYP3A2 proteins was also confirmed in cultured rat TAECs using a polyclonal anti-CYP antibody and immunofluorescence microscopy. In contrast, the formation rate of N-oxide at pH 8.4 was higher than that at pH 7.4. Inhibition of N-oxide formation by methimazole was found to be the best model of competitive inhibition yielding an apparent K i value of 0.80 µmol/L, demonstrating that N-oxidation was catalyzed by FMO in rat TAECs. These results suggest that rat TAEC enzymes can convert substrates of exogenous origin such as imipramine, indicating that TAECs have an important function for metabolic products, besides hepatic cells.

Basic N-interlinked imipramines show apoptotic activity against malignant cells including Burkitt's lymphoma.

We here report the synthesis of ethylene glycol N-interlinked imipramine dimers of various lengths from the tricyclic antidepressant desipramine via an amide coupling reaction followed by reduction with lithium aluminium hydride. The target molecules were found to be potent inhibitors of cellular viability while inducing cell type specific death mechanisms in three cancer cell lines including a highly chemoresistant Burkitt's lymphoma cell line. Basic amine analogues were found to be important for increased potency. Imipramine and desipramine were also tested for apoptotic activity and were found to be much less active than the novel dimeric compounds. Imipramine dimers were only found to be moderate inhibitors of the human serotonin transporter (hSERT) having IC(50) values in the micromolar region whilst the induction of cell death occurred independently of hSERT expression. These results demonstrate the potential of newly designed and synthesised imipramines derivatives for use against malignant cells, including those resistant to standard chemotherapy.

Neuron density and serotonin receptor binding in prefrontal cortex in suicide.

Although serotonin receptor and cytoarchitectonic alterations are reported in prefrontal cortex (PFC) in suicide and depression, no study has considered binding relative to neuron density. Therefore, we measured neuron density and serotonin transporter (SERT), 5-HT1A and 5-HT2A binding in matched suicides and controls. Suicides and normal controls (n=15 matched pairs) were psychiatrically characterized. Neuron density and binding were determined in dorsal [Brodmann area (BA) 9] and ventral (BA 47) PFC by stereology and quantitative autoradiography in near-adjacent sections. Binding index was defined as the ratio of receptor binding to neuron density. Suicides had lower neuron density in the gyrus of both areas. The binding index was lower for SERT in BA 47 but not in BA9; the 5-HT1A binding index was higher in BA 9 but not in BA 47, while the 5-HT2A binding index was not different between groups. SERT binding was lower in suicides in BA 47 but not BA 9, while 5-HT1A binding was higher in BA 9 but not BA 47. SERT binding negatively correlated with 5-HT1A binding in BA 47 in suicides. Neuron density decreased with age. The 5-HT1A binding index was higher in females than males. We found lower neuron density and lower SERT binding index in both PFC regions in suicides. More 5-HT1A binding with less SERT binding and the negative correlation in depressed suicides suggests post-synaptic receptor up-regulation, and it is independent of the difference in neuron density. Thus, abnormalities in both cortical neurons and in their serotonergic innervation are present in suicides and future studies will need to determine whether cortical changes reflect the trophic effect of altered serotonin innervation.

Serotonergic and noradrenergic pathways are required for the anxiolytic-like and antidepressant-like behavioral effects of repeated vagal nerve stimulation in rats.

BACKGROUND: Vagal nerve stimulation (VNS) is used for treatment-refractory depression, but there are few preclinical studies of its effects when administered repeatedly over time using clinically relevant stimulation parameters in nonanesthetized animals. METHODS: The novelty-suppressed feeding test (NSFT) and forced swim test (FST) were used to evaluate the anxiolytic- and antidepressant-like potential of VNS in rats, respectively. The behavioral effects of VNS were compared with those of desipramine (DMI; 10 mg/kg/day) and sertraline (7.5 mg/kg/day) administered via osmotic minipump. Such experiments were carried out in intact rats as well as those that had selective destruction of either serotonin or noradrenergic neurons in brain caused by the neurotoxins, 5,7-dihyroxytryptamine (5,7-DHT), or 6-hydroxydopamine (6-OHDA). RESULTS: Repeated administration of VNS, DMI, and sertraline decreased latency to feed in the NSFT. In the FST, repeated VNS, DMI, and sertraline caused decreased immobility; the VNS-induced decrease in immobility resulted from increases in both swimming and climbing behaviors. Effects of VNS and sertraline, but not DMI, in both the NSFT and the FST were abolished in rats treated with 5,7-DHT. Effects of DMI in both behavioral tests, but not those of sertraline, were abolished in 6-OHDA treated rats. VNS effects on immobility and climbing in the FST were not blocked in the 6-OHDA-treated rats. There was no significant difference in locomotor activity caused by any of the treatments or by the lesions. CONCLUSIONS: Serotonergic nerves are required for repeated VNS-induced anxiolytic- and antidepressant-like effects. Noradrenergic nerves can also be activated by VNS to cause its anxiolytic-like effect.

Determination of moxifloxacin in human plasma, plasma ultrafiltrate, and cerebrospinal fluid by a rapid and simple liquid chromatography- tandem mass spectrometry method.

Moxifloxacin (MFX) is a useful agent in the treatment of multi-drug-resistant tuberculosis (MDR-TB). At Tuberculosis Centre Beatrixoord, a referral center for tuberculosis in the Netherlands, approximately 36% of the patients have received MFX as treatment. Based on the variability of MFX AUC, the variability of in vitro susceptibility to MFX of M. tuberculosis, and the variability of penetration into sanctuary sites, measuring the concentration of MFX in plasma and cerebrospinal fluid (CSF) could be recommended. Therefore, a rapid and validated liquid chromatography-tandem mass spectrometry (LC-MS-MS) analyzing method with a simple pretreatment procedure was developed for therapeutic drug monitoring of MFX in human plasma and CSF. Because of the potential influence of protein binding on efficacy, we decided to determine both bound and unbound (ultrafiltrate) fraction of MFX. The calibration curves were linear in the therapeutic range of 0.05 to 5.0 mg/L plasma and CSF with CV in the range of -5.4% to 9.3%. MFX ultrafiltrate samples could be determined with the same method setup for analysis of MFX in CSF. The LC-MS-MS method developed in this study is suitable for monitoring MFX in human plasma, plasma ultrafiltrate, and CSF.

Sequential metabolism of secondary alkyl amines to metabolic-intermediate complexes: opposing roles for the secondary hydroxylamine and primary amine metabolites of desipramine, (s)-fluoxetine, and N-desmethyldiltiazem.

Three secondary amines desipramine (DES), (S)-fluoxetine [(S)-FLX], and N-desmethyldiltiazem (MA) undergo N-hydroxylation to the corresponding secondary hydroxylamines [N-hydroxydesipramine, (S)-N-hydroxyfluoxetine, and N-hydroxy-N-desmethyldiltiazem] by cytochromes P450 2C11, 2C19, and 3A4, respectively. The expected primary amine products, N-desmethyldesipramine, (S)-norfluoxetine, and N,N-didesmethyldiltiazem, are also observed. The formation of metabolic-intermediate (MI) complexes from these substrates and metabolites was examined. In each example, the initial rates of MI complex accumulation followed the order secondary hydroxylamine > secondary amine >> primary amine, suggesting that the primary amine metabolites do not contribute to formation of MI complexes from these secondary amines. Furthermore, the primary amine metabolites, which accumulate in incubations of the secondary amines, inhibit MI complex formation. Mass balance studies provided estimates of the product ratios of N-dealkylation to N-hydroxylation. The ratios were 2.9 (DES-CYP2C11), 3.6 [(S)-FLX-CYP2C19], and 0.8 (MA-CYP3A4), indicating that secondary hydroxylamines are significant metabolites of the P450-mediated metabolism of secondary alkyl amines. Parallel studies with N-methyl-d(3)-desipramine and CYP2C11 demonstrated significant isotopically sensitive switching from N-demethylation to N-hydroxylation. These findings demonstrate that the major pathway to MI complex formation from these secondary amines arises from N-hydroxylation rather than N-dealkylation and that the primary amines are significant competitive inhibitors of MI complex formation.

Binding and orientation of tricyclic antidepressants within the central substrate site of the human serotonin transporter.

Tricyclic antidepressants (TCAs) have been used for decades, but their orientation within and molecular interactions with their primary target is yet unsettled. The recent finding of a TCA binding site in the extracellular vestibule of the bacterial leucine transporter 11 A above the central site has prompted debate about whether this vestibular site in the bacterial transporter is applicable to binding of antidepressants to their relevant physiological target, the human serotonin transporter (hSERT). We present an experimentally validated structural model of imipramine and analogous TCAs in the central substrate binding site of hSERT. Two possible binding modes were observed from induced fit docking calculations. We experimentally validated a single binding mode by combining mutagenesis of hSERT with uptake inhibition studies of different TCA analogs according to the paired mutation ligand analog complementation paradigm. Using this experimental method, we identify a salt bridge between the tertiary aliphatic amine and Asp(98). Furthermore, the 7-position of the imipramine ring is found vicinal to Phe(335), and the pocket lined by Ala(173) and Thr(439) is utilized by 3-substituents. These protein-ligand contact points unambiguously orient the TCA within the central binding site and reveal differences between substrate binding and inhibitor binding, giving important clues to the inhibition mechanism. Consonant with the well established competitive inhibition of uptake by TCAs, the resulting binding site for TCAs in hSERT is fully overlapping with the serotonin binding site in hSERT and dissimilar to the low affinity noncompetitive TCA site reported in the leucine transporter (LeuT).

Selective alterations of the CB1 receptors and the fatty acid amide hydrolase in the ventral striatum of alcoholics and suicides.

Recent studies in rodents have suggested a role for the central endocannabinoid system in the regulation of mood and alcohol related behaviors. Alcohol use disorder is often associated with suicidal behavior. In the present study, we examined whether abnormalities in the endocannabinoid system in the ventral striatum are associated with alcohol dependence and suicide. The levels of CB1 receptors, receptor-mediated G-protein signaling, and activity and level of the fatty acid amide hydrolase (FAAH) were analyzed postmortem in the ventral striatum of alcohol-dependent nonsuicides (CA, n=9), alcohol-dependent suicides (AS, n=9) and nonpsychiatric controls (C, n=9). All subjects underwent a psychological autopsy, and toxicological and neuropathological examinations. The levels of the CB1 receptors and the CB1 receptor-mediated G-protein signaling were significantly lower in the ventral striatum of CA compared to the control group. However, these parameters were elevated in AS when compared to CA group. The activity of FAAH enzyme was lower in CA compared to the control group while it was found to be significantly higher in AS compared with CA group. These findings suggest that alcohol dependence is associated with the downregulation of the CB1 receptors, while suicide is linked to the upregulation of these receptors in the ventral striatum. Alteration in the activity of FAAH enzyme that regulates the anandamide (AEA) content might in turn explain differences in the CB1 receptor function in alcohol dependence and suicide. These findings may have etiological and therapeutic implications for the treatment of alcohol addiction and suicidal behavior.

Identification of novel allosteric nonpeptidergic inhibitors of the human cytomegalovirus-encoded chemokine receptor US28.

Human cytomegalovirus (HCMV) is a widespread human pathogen, possessing onco-modulatory properties. Constitutive signaling of the HCMV-encoded chemokine receptor US28 and its ability to bind a broad spectrum of chemokines might facilitate HCMV-associated tumor progression. Novel nonpeptidergic chemotypes were identified as neutral antagonists or inverse agonists on US28, that allosterically inhibit chemokine binding to US28.

Synthesis of a quaternary bis derivative of imipramine as a novel compound with potential anti-enuretic effect.

OBJECTIVES: Imipramine has been used for over four decades (early reports in 1960s) for the treatment of nocturnal enuresis, although the reason for its effect is not clear. Imipramine is a tertiary amine, which may act both in the periphery and/or pass through the blood-brain barrier (BBB) in unionized form and exhibit a central effect. Since imipramine has anti-cholinergic properties, some believe it may exert its anti-enuretic effect by affecting peripheral cholinergic receptors, i.e. its anti-enuretic effect may be due to peripheral anti-cholinergic properties, whereas others think it can pass through the BBB and interact with central nervous system (CNS) receptors. If the anti-enuretic effect of imipramine is due to its peripheral anti-cholinergic effects, its entrance into the CNS is unnecessary. Therefore, the synthesis of a form of imipramine that can exhibit peripheral anti-cholinergic effects but does not have CNS adverse effects would have a safer drug profile in this case. On the other hand, if the anti-enuretic effect of imipramine is primarily due to its action on the CNS, a form of imipramine that cannot pass through the BBB has no effect on nocturnal enuresis treatment and thus may help to clarify the mechanism of action of imipramine in nocturnal enuresis treatment. METHODS: This article describes the synthesis and evaluation of the anti-cholinergic effect of a new bis derivative of imipramine, which contains two imipramine units in its structure. KEY FINDINGS: The compound exhibited anti-cholinergic activity comparable with that of imipramine on isolated guinea pig ileum. CONCLUSIONS: Being a quaternary ammonium, this compound is not expected to be able to cross the BBB and thus would cause fewer CNS side effects.

Deletion of the mouse Fmo1 gene results in enhanced pharmacological behavioural responses to imipramine.

OBJECTIVES: Many drugs are the subject of multipathway oxidative metabolism catalyzed by one or more cytochromes P450 or flavin-containing monooxygenases (FMOs). This complicates assessment of the role of individual enzymes in metabolizing the drug and, hence, in understanding its pharmacogenetics. To define the role of FMOs in drug metabolism, we produced FMO-deficient mice. METHODS: An Fmo1(-/-), Fmo2(-/-), Fmo4(-/-) mouse line was produced by using chromosomal engineering and Cre-loxP technology. To assess the utility of the mutant mouse line, it was used to investigate the role of FMO in the metabolism of and response to the antidepressant imipramine, which has four major metabolites, three produced by cytochromes P450 and one, imipramine N-oxide, solely by FMO1. RESULTS: On treatment with imipramine, wild-type mice became sedated and produced imipramine N-oxide in the brain and other tissues. In contrast, knockout mice did not produce imipramine N-oxide, but showed exaggerated pharmacological behavioural responses, such as tremor and body spasm, and had a higher concentration of the parent compound imipramine in the serum and kidney and there was an increase in desipramine in the brain. CONCLUSION: The absence of FMO1-mediated N-oxidation of imipramine results in enhanced central nervous system effects of the drug. The results provide insights into the metabolism of imipramine in the brain and may explain the basis of the adverse reactions to the drug seen in some patients. The knockout mouse line will provide a valuable resource for defining the role of FMO1 in the metabolism of drugs and other foreign chemicals.

Differential regulation of serotonin-1A receptor-stimulated [35S]GTP gamma S binding in the dorsal raphe nucleus by citalopram and escitalopram.

The effect of chronic citalopram or escitalopram administration on 5-HT1A receptor function in the dorsal raphe nucleus was determined by measuring [35S]GTP gamma S binding stimulated by the 5-HT1A receptor agonist (R)-(+)-8-OH-DPAT (1nM-10 microM). Although chronic administration of citalopram or escitalopram has been shown to desensitize somatodendritic 5-HT1A autoreceptors, we found that escitalopram treatment decreased the efficacy of 5-HT1A receptors to activate G proteins, whereas citalopram treatment did not. The binding of [3H]8-OH-DPAT to the coupled, high affinity agonist state of the receptor was not altered by either treatment. Interestingly, escitalopram administration resulted in greater occupancy of serotonin transporter sites as measured by the inhibition of [3H]cyanoimipramine binding. As the binding and action of escitalopram is limited by the inactive enantiomer R-citalopram present in racemic citalopram, we propose that the regulation of 5-HT1A receptor function in the dorsal raphe nucleus at the level of receptor-G protein interaction may be a result of greater inhibition of the serotonin transporter by escitalopram.

Photophysics and photochemistry of imipramine, desimipramine, and clomipramine in several solvents: a fluorescence, 266 nm laser flash, and theoretical study.

Imipramine (IPA) and its derivatives are used widely for the treatment of depression and other mental disorders. Although there are more than 20 FDA-approved antidepressant drugs, the search continues for better compounds with fewer deleterious side effects and higher efficacy. Over the past decade, several classes of antipsychotic drugs have been developed, which-in spite of their structural diversity-share an ability to modulate neurotransmission and to produce undesirable side effects. Phototoxicity is one of the most important side effects noted in treatment with tricyclic antidepressants (TCAs), but its mechanism has not yet been elucidated. To develop new knowledge regarding the relationship between the structure and the photophysics of these TCAs, we measured the photophysical properties of IPA, desimipramine (DIPA), and clomipramine (CIPA) in different solvents. The electronic configurations for the ground and the first excited singlet states were calculated using the AM1/RHF/CI and the AM1/RHF/HE semiempirical quantum theoretical methods, respectively. The ground-state properties are solvent-independent, while the emission maxima are red-shifted with increasing solvent polarity/polarizability. However, the fluorescence quantum yield is relatively low in all of the tested solvents (phif<0.02). The primary transient intermediates produced by 266 nm high-intensity laser photolysis are the solvated electron and the corresponding radical cation, with a negligible contribution of triplet-triplet absorption. The properties determined for the primary transients generated with a 266 nm laser flash are consistent with the photodamaging effects generated through a limited radical mechanism.

Architectonic distribution of the serotonin transporter within the orbitofrontal cortex of the vervet monkey.

To elucidate the organization of the serotoninergic innervation within the orbitofrontal cortex (OFC), serotonin transporter (SERT) density was quantified by autoradiography using [(3)H]cyanoimipramine binding. In six adult vervet monkeys, 15 architectonic areas were delineated according to cytoarchitectonic (Nissl), myeloarchitectonic (Gallyas) and chemoarchitectonic (acetylcholinesterase) criteria to assess SERT distribution at two levels of organization: cortical area and cortical type. For cortical type, the 15 areas were evenly divided into three different categories primarily based upon the degree of granularization of layer IV: agranular, dysgranular, and granular. Within agranular and dysgranular, but not granular cortical types, SERT density was area-specific and progressively decreased in a medial to lateral gradient. Across cortical types, SERT density decreased in a caudal to rostral gradient: agranular>dysgranular>granular. A similar caudal to rostral gradient was seen when serotonin content was measured (using high performance liquid chromatography) in areas representative of each cortical type. Collectively, these results suggest that the serotoninergic innervation is organized according to both cortical type and area, and is thus structured to differentially modulate information processing within the OFC.

Pharmacological properties of the active metabolites of the antidepressants desipramine and citalopram.

Although major metabolites of some antidepressant drugs are known to be active, their pharmacological effects are poorly characterized. Two of the most selective antidepressants, desipramine (selectively inhibits norepinephrine reuptake) and citalopram (selectively inhibits serotonin reuptake) are frequently used in animal studies of antidepressant action, as well as being useful therapeutically. The primary aim of this study was to determine the affinity of desmethyldesipramine, an active metabolite of desipramine, for the rat norepinephrine and serotonin transporters, as well as for the rat alpha(2)-adrenoceptor. The pharmacological characteristics of desmethyldesipramine and desmethylcitalopram, an active metabolite of citalopram, were also determined for various human transporters and neurotransmitter receptors. Competition binding studies using [(3)H]nisoxetine and [(3)H]citalopram showed desipramine to be 25 times more selective for the rat norepinephrine as compared to serotonin transporter (6.2 nM vs. 158 nM) whereas desmethyldesipramine is 12 times more selective for the serotonin over the norepinephrine transporter (12.8 nM vs. 153 nM). Interestingly, the affinity of desmethyldesipramine for the serotonin transporter is similar to the affinity of desipramine for the norepinephrine transporter. Desipramine and desmethyldesipramine were found to have a lower affinity for the rat alpha(2A(D))-adrenoceptor than the transporters, suggesting that this receptor is not a major site of action for either compound. Thus, the pharmacological effects of desipramine in rats may be attributed not only to the inhibition of the norepinephrine transporter by desipramine but also to the inhibition of serotonin transporter by the active metabolite desmethyldesipramine.

Appropriate dosing regimens for treating juvenile rats with desipramine for neuropharmacological and behavioral studies.

The tricyclic antidepressants, including desipramine (DMI), are no better than placebo in treating childhood and adolescent depression, but are effective in adult depression. Animal studies comparing the effects of DMI in juveniles and adults are complicated by age-related variations in elimination rates. Thus, different dosing regiments are needed to achieve similar brain drug levels in juvenile and adult rats. We compared the half-life of DMI as well as the brain and serum concentrations of DMI and its active metabolite desmethyldesipramine in juvenile and adult rats after various drug administration paradigms. After acute i.p. administration DMI is eliminated from the brain more slowly in postnatal day (PND) 21 and 28 rats as compared to adults. After chronic i.p. administration (for 4-5 days between PND 9 and 28), lower doses of DMI are needed with juvenile rats to obtain the same brain DMI concentrations as adults. By contrast, 2 weeks of continuous drug delivery (minipump) to PND 21-35 and adult rats result in similar brain DMI concentrations. Thus, the pharmacokinetic properties of DMI varies with the age of the animal and dosing of DMI and needs to be carefully adjusted in order to have appropriate brain levels of the drug.

Differential neurotoxicity of tricyclic antidepressants and novel derivatives in vitro in a dorsal root ganglion cell culture model.

BACKGROUND AND OBJECTIVE: Tricyclic antidepressants are commonly employed orally to treat major depressive disorders and have been shown to be of substantial benefit in various chronic pain conditions. Among other properties they are potent Na+ channel blockers in vitro and show local anaesthetic properties in vivo. The present study aimed to determine their differential neurotoxicity, and that of novel derivatives as prerequisite for their potential use in regional anaesthesia. METHODS: To directly test neurotoxicity in adult peripheral neurons, the culture model of dissociated adult rat primary sensory neurons was employed. Neurons were incubated for 24 h with amitriptyline, N-methyl-amitriptyline, doxepin, N-methyl-doxepin, N-propyl-doxepin, desipramine, imipramine and trimipramine at 100 mumol, and at concentrations correlating to their respective potency in blocking sodium channels. RESULTS: All investigated substances showed considerable neurotoxic potency as represented in significantly decreased neuron numbers in cultures as compared to controls. Specifically, doxepin was more neurotoxic than amitriptyline, and both imipramine and trimipramine were more toxic than desipramine or amitriptyline. Novel derivatives of tricyclic antidepressants were, in general, more toxic than the parent compound. CONCLUSIONS: Tricyclic antidepressants and novel derivatives thereof show differential neurotoxic potential in vitro. The rank order of toxicity relative to sodium channel blocking potency was desipramine < amitriptyline < N-methyl amitriptyline < doxepin < trimipramine < imipramine < N-methyl doxepin < N-propyl doxepin.