A novel drug repurposing approach for non-small cell lung cancer using deep learning.

Drug repurposing is an attractive and pragmatic way offering reduced risks and development time in the complicated process of drug discovery. In the past, drug repurposing has been largely accidental and serendipitous. The most successful examples so far have not involved a systematic approach. Nowadays, remarkable advances in drugs, diseases and bioinformatic knowledge are offering great opportunities for designing novel drug repurposing approach through comprehensive understanding of drug information. In this study, we introduced a novel drug repurposing approach based on transcriptomic data and chemical structures using deep learning. One strong candidate for repurposing has been identified. Pimozide is an anti-dyskinesia agent that is used for the suppression of motor and phonic tics in patients with Tourette's Disorder. However, our pipeline proposed it as a strong candidate for treating non-small cell lung cancer. The cytotoxicity of pimozide against A549 cell lines has been validated.

The Novel Small Molecule TRVA242 Stabilizes Neuromuscular Junction Defects in Multiple Animal Models of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder in which the neuromuscular junction progressively degenerates, leading to movement difficulties, paralysis, and eventually death. ALS is currently being treated by only two FDA-approved drugs with modest efficacy in slowing disease progression. Often, the translation of preclinical findings to bedside terminates prematurely as the evaluation of potential therapeutic compounds focuses on a single study or a single animal model. To circumscribe these issues, we screened 3,765 novel small molecule derivatives of pimozide, a recently identified repurposed neuroleptic for ALS, in Caenorhabditis elegans, confirmed the hits in zebrafish and validated the most active compounds in mouse genetic models. Out of the 27 small molecules identified from the high-throughput screen in worms, 4 were found to recover locomotor defects in C. elegans and genetic zebrafish models of ALS. TRVA242 was identified as the most potent compound as it significantly improved efficiency in rescuing locomotor, motorneuron, and neuromuscular junction synaptic deficits in a C. elegans TDP-43 model and in multiple zebrafish genetic (TDP-43, SOD1, and C9ORF72) models of ALS. The actions of TRVA242 were also conserved in a mammalian model as it also stabilized neuromuscular junction deficits in a mouse SOD1 model of ALS. Compounds such as TRVA242 therefore represent new potential therapeutics for the treatment of ALS.

Pharmacological profile of neuroleptics at human monoamine transporters.

Using radioligand binding techniques, we determined the equilibrium dissociation constants (K(D)) for 37 neuroleptics and one metabolite of a neuroleptic (haloperidol metabolite) for the human serotonin, norepinephrine, and dopamine transporters with [3H]imipramine, [3H]nisoxetine, and [3H]WIN35428, respectively. Among neuroleptics, the four most potent compounds at the human serotonin transporter were triflupromazine, fluperlapine, chlorpromazine, and ziprasidone (K(D) 24-39 nM); and at the norepinephrine transporter, chlorpromazine, zotepine, chlorprothixene, and promazine (K(D) 19-25 nM). At the human dopamine transporter, only pimozide (K(D) = 69+/-3) ziprasidone (K(D) = 76+/-5) had notable potency. These data may be useful in predicting therapeutic and adverse effects, including drug interactions of neuroleptics.

Identification and characterization of human cytochrome P450 isoforms interacting with pimozide.

Using human liver microsomes (HLMs) and recombinant human cytochrome P450 (CYP450) isoforms, we identified the major route of pimozide metabolism, the CYP450 isoforms involved, and documented the inhibitory effect of pimozide on CYP450 isoforms. Pimozide was predominantly N-dealkylated to 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one (DHPBI). The formation rate of DHPBI showed biphasic kinetics in HLMs, which suggests the participation of at least two activities. These were characterized as high-affinity (K(m1) and Vmax1) and low-affinity (K(m2) and Vmax2) components. The ratio of Vmax1 (14 pmol/min/mg protein)/K(m1) (0.73 microM) was 5.2 times higher than the ratio of Vmax2 (244 pmol/min/mg protein)/K(m2) (34 microM). K(m2) was 91 times higher than K(m1). The formation rate of DHPBI from 25 microM pimozide in nine human livers correlated significantly with the catalytic activity of CYP3A (Spearman r = 0.79, P = .028), but not with other isoforms. Potent inhibition of DHPBI formation from 10 microM pimozide was observed with ketoconazole (88%), troleandomycin (79%), furafylline (48%) and a combination of furafylline and ketoconazole (96%). Recombinant human CYP3A4 catalyzed DHPBI formation from 10 microM pimozide at the highest rate (V = 2.2 +/- 0.89 pmol/min/pmol P450) followed by CYP1A2 (V = 0.23 +/- 0.08 pmol/min/pmol P450), but other isoforms tested did not. The K(m) values derived with recombinant CYP3A4 and CYP1A2 were 5.7 microM and 36.1 microM, respectively. Pimozide itself was a potent inhibitor of CYP2D6 in HLMs when preincubated for 15 min (Ki = 0.75 +/- 0.98 microM) and a moderate inhibitor of CYP3A (Ki = 76.7 +/- 34.5 microM), with no significant effect on other isoforms tested. Our results suggest that pimozide metabolism is catalyzed mainly by CYP3A, but CYP1A2 also contributes. Pimozide metabolism is likely to be subject to interindividual variability in CYP3A and CYP1A2 expression and to drug interactions involving these isoforms. Pimozide itself may inhibit the metabolism of drugs that are substrates of CYP2D6.

Partition coefficients of dopamine antagonists in brain membranes and liposomes.

Partition coefficients, Kp of dopamine antagonists, spiperone, haloperidol, domperidone and pimozide were determined in caudate nucleus microsomal membranes and in liposomes from membrane lipids. Kp values were measured as a function of temperature and the thermodynamics parameters for the transfer of the drugs from the aqueous medium to the lipid bilayer were evaluated. Partition in native membranes or in liposomes formed from the membrane lipids is not strongly dependent on temperature over the range from 8 to 37 degrees. The Kp values for spiperone, haloperidol and domperidone in membrane are 32 +/- 6, 192 +/- 11 and 308 +/- 40 respectively, whereas the equivalent values in liposomes are much higher: 195 +/- 12, 558 +/- 16 and 316 +/- 16. In contrast, for pimozide, the Kp values in membranes are higher than in liposomes: 1097 +/- 11 for microsomes and 662 +/- 10 for liposomes. Partition values in natural membranes decrease sequentially as follows: pimozide greater than domperidone greater than haloperidol greater than spiperone. Membranes rich in cholesterol show lower partition coefficients for haloperidol. The interaction of the antagonists with the bilayer is associated with small enthalpy changes and large increases in entropy, as expected for hydrophobic interactions. We conclude that the partition coefficients of the drugs studied for membranes and membranes lipids are very different from those reported for octanol/water and the latter values should not be used to estimate drug partition into membranes.

Interaction of dopamine receptor ligands with subtypes of the opiate receptor.

There are currently several studies in which individual dopamine receptor ligands have been reported to bind with relatively low affinity to opiate receptors. To extend these studies, and to examine the opiate receptor subclass selectivity of such agents, we have examined the ability of six dopamine receptor ligands (prochlorperazine, chlorpromazine, haloperidol, bromocriptine, pimozide and metoclopramide) to compete with four tritiated tracers - [3H]naloxone, [3H][D-Ala2,D-Leu5]enkephalin, [3H]morphine and [3H]ethylketocyclazocine - for binding to rat brain membrane opiate receptors. The dopamine receptor ligands displaced the labelled opiates in a dose-dependent manner, with ED50 values of 3 microM to 3 mM. Pimozide was consistently the most potent (ED50 3-14 microM), and metoclopramide the least potent (ED50 35 microM to 3.5 mM). Dopamine receptor agonists and antagonists thus interact with opiate receptors with no clear subclass selectivity, and with similar hierarchies of inhibitory potency in each of the various opiate receptor systems.

An hypothesis of the molecular structure of the dopamine receptor.

Neurotensin has psychopharmacological properties similar to dopamine receptor blocking drugs. A Chou and Fasman analysis of the primary sequence suggests that the sequence 1-6 forms an alpha-helix broken by pro (7) and 9-12 forms a beta-turn. This allows the peptide molecule to form an amphoteric structure with, on one side, the evenly space array - p glu - glu - arg - arg - ( delta- - + +) which is self-complementary. Thus, two molecules of neurotensin placed head to tail can form a Kusnetsov-Ghokov grid with four cross-links (p glu and glu to arg - arg) x 2. The walls of a shadow potential receptor cup are formed by asn(5), pro(7), ile(12) and pro(10) on each side. CPK model building experiments indicate that this structure is complementary to a wide range of dopamine agonists and antagonists. Therefore, the hypothesis is presented that neurotensin may mimic part of the DA receptor protein. Thus it may form a 'false' receptor and trap dopamine molecules, thus diminishing the dopamine effect. Similarities between this proposed structure and a model of the molecular structure of the acetylcholine receptor are detailed.

Lack of behavioral supersensitivity to d-amphetamine after pimozide withdrawal. A trial with schizophrenic patients.

The dopamine hypothesis of schizophrenia claims that increased dopamine activity underlies psychotic behavior. This hypothesis gets major support from the reported d-amphetamine-induced worsening of psychosis, because amphetamine increases dopamine activity in the brain. Dopamine receptor supersensitivity has been shown to be present in animals during the postneuroleptic period. In this study the postulated relationships between psychotic decompensation as observed after d-amphetamine infusion and the dopamine receptor supersensitivity expected to be present during the neuroleptic withdrawal period were examined. Twenty milligrams of d-amphetamine administered intravenously did not cause a stronger psychotogenic effect in 12 schizophrenic patients. One week after discontinuation of pimozide treatment, the d-amphetamine-induced change as indicated by the Brief Psychiatric Rating Scale (BPRS) paranoid disturbance cluster score, was not significantly different from the response to a similar infusion during the drug-free state. Unexpectedly, the increase in the BPRS mannerisms and posturing item and in the pulse rate response to d-amphetamine were decreased. These results raise questions about the role of dopamine in d-amphetamine effects and suggest postneuroleptic dopamine receptor subsensitivity. They challenge a simple dopamine hypothesis of schizophrenia.

The regional localization of R28935 in the cat brain as dependent on the route of administration.

Intravenous injection of the antihypertensive agent R2835 and its pharmacologically less active threo-isomer R29814 resulted in a distribution profile in the cat brain which differed from the regional localization after administration via the left vertebral artery. Although the two isomers had the same physico-chemical properties, R28935 penetrated more readily into the CNS. Intravenous administration resulted in almost equal levels in all brain parts, whereas after injection into the vertebral artery caudal structures contained more of both compounds that rostral structures. Differences existed between the concentrations in homotopic brain areas, especially in the brain stem. From comparison of the levels of R28935 after injection of an equiactive dose either i.v. or into the vertebral artery it is tempting to speculate that the mesencephalic tegmentum, the nucleus of the solitary tract, the inferior colliculi and/or the locus coeruleus are possible sites of the hypotensive action.

Dynamic cation-exchange systems for the separation of drugs derived from butyrophenone and diphenylpiperidine by high-performance liquid chromatography and applied in the determination of halopemide in plasma.

Dynamic (solvent generated) cation-exchange systems for the separation of drugs and main metabolites derived from butyrophenone and diphenylpiperidine (haloperidol, pimozide, halopemide) were investigated. The effect of organic modifier, detergent, counter-ion concentration and of the pH on the retention has been determined. The results show that variation of these parameters permits adjustment of the retention of these drugs over a wide range. The dynamic cation-exchange system developed was applied to the determination of halopemide and its main metabolite in plasma. The precision and detection limit of the method and the extraction efficiency were established. The time course of halopemide and plasma levels of patients chronically receiving halopemide are reported.

Pimozide: a review of its pharmacological properties and therapeutic uses in psychiatry.

Pimozide 1-(1-[4,4-bis(4-fluorophenyl)butyl]-4-peperidinyl)-2-benzimidazolone, is the first of a new series of psychotropic drugs, the kiphenylbutylpiperidines. It is advocated for once-daily use as maintenance therapy in chronic schizophrenia and for the treatment of psychic and functional disorders induced by personality traits. Published data suggest that in chronic schizophrenia, pimozide 4 to 6mg daily is indistinguishable from maintenance doses of chlorpromazine, fluphenazine, flupenthixol, perphenazine, or thioidazine. Patient groups have usually been to small to allow statistically significant differences to be apparent, but in some trials pimozide was significantly superior to trifluoperzine and to haloperidol. On present evidence, pimozide has no place in the hyperactive, aggressive type of patient or in treating the acute phase of schizophrenia, probably because of its relative lack of sedative properties compared with many antipsychotic drugs. The incidence and severity of extrapyramidal reactions with pimozide are low, but suitably designed controlled studies are needed to determine whether its use leads to a reduction in the requirement for antiparkinsonian medication. In anxious patients, pimozide seems to offer no advantages over currently available anxiolytic agents, either in terms of efficacy or incidence of side-effects. Claims for a specific effect against anxiety associated with psychosis or disturbed personality traits remain unproven.