Discovery of a 1-isopropyltetrahydroisoquinoline derivative as an orally active N-type calcium channel blocker for neuropathic pain

Ogiyama, Takashi; Yonezawa, Koichi; Inoue, Makoto; Sugano, Yukihito; Gotoh, Takayasu; Kiso, Tetsuo; Koakutsu, Akiko; Kakimoto, Shuichiro; Shishikura, Jun-ichi

doi:10.1016/j.bmc.2015.05.030

Cited by 9 publications

(5 citation statements)

References 39 publications

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“…Isoquinolines and saturated congeners, such as 1,2-dihydroisoquinolines, on the other hand, are also of biological importance. They are also implicated in the treatment of cancer (Inoue et al, 2005), neuropathic pains (Ogiyama et al, 2015), bacterial infections (Solecka et al, 2009) and depressive illnesses (Brogden et al, 1979). Isoquinoline derivatives are currently of interest as possible neurotoxins in the treatment of Parkinson's disease, since they share a structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite the 1-methyl-4-phenylpyridinium ion (MPP + ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis, crystal structure and docking studies of tetracyclic 10-iodo-1,2-dihydroisoquinolino[2,1-b][1,2,4]benzothiadiazine 12,12-dioxide and its precursors

et al. 2020

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The title compound, 10-iodo-1,2-dihydroisoquinolino[2,1-b][1,2,4]benzothiadiazine 12,12-dioxide, C15H11IN2O2S (8), was synthesized via the metal-free intramolecular N-iodosuccinimide (NIS)-mediated radical oxidative sp 3-C—H aminative cyclization of 2-(2′-aminobenzenesulfonyl)-1,3,4-trihydroisoquinoline, C15H16N2O2S (7). The amino adduct 7 was prepared via a two-step reaction, starting from the condensation of 2-nitrobenzenesulfonyl chloride (4) with 1,2,3,4-tetrahydroisoquinoline (5), to afford 2-(2′-nitrobenzenesulfonyl)-1,3,4-trihydroisoquinoline, C15H14N2O4S (6), in 82% yield. The catalytic hydrogenation of 6 with hydrogen gas, in the presence of 10% palladium-on-charcoal catalyst, furnished 7. Products 6–8 were characterized by their melting points, IR and NMR (1H and 13C) spectroscopy, and single-crystal X-ray diffraction. The three compounds crystallized in the monoclinic space group, with 7 exhibiting classical intramolecular hydrogen bonds of 2.16 and 2.26 Å. All three crystal structures exhibit centrosymmetric pairs of intermolecular C—H...π(ring) and/or π–π stacking interactions. The docking studies of molecules 6, 7 and 8 with deoxyribonucleic acid (PDB id: 1ZEW) revealed minor-groove binding behaviours without intercalation, with 7 presenting the most favourable global energy of the three molecules. Nonetheless, molecule 8 interacted strongly with the DNA macromolecule, with an attractive van der Waals energy of −15.53 kcal mol−1.

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Section: Introductionmentioning

confidence: 99%

Synthesis, crystal structure and docking studies of tetracyclic 10-iodo-1,2-dihydroisoquinolino[2,1-b][1,2,4]benzothiadiazine 12,12-dioxide and its precursors

et al. 2020

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“…Among the 70 compounds sharing the same alert scaffold, 60 compounds exhibited TDI but 10 did not. Although this fragment was not a confirmed structural alert in the source literature, our analysis results demonstrated that it can be used as a structural alert for CYP3A4 TDI. Chemicals with fragments that have N attached with cyclopropane and other functional groups such as N -methylcyclopropanimine and N -(2-chlorobenzyl)cyclopropanamine tended to cause CYP3A4 TDI as reported in the literature. − Chemicals containing 8-methylquinoline were more possible to be time-dependent inhibitors of CYP3A4 due to the formation of an active metabolite capable of binding irreversibly to the CYP enzymes .…”

Section: Discussionmentioning

confidence: 60%

Development of In Silico Models for Predicting Potential Time-Dependent Inhibitors of Cytochrome P450 3A4

et al. 2022

Mol. Pharmaceutics

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Cytochrome P450 3A4 (CYP3A4) is one of the major drug metabolizing enzymes in the human body and metabolizes ∼30–50% of clinically used drugs. Inhibition of CYP3A4 must always be considered in the development of new drugs. Time-dependent inhibition (TDI) is an important P450 inhibition type that could cause undesired drug–drug interactions. Therefore, identification of CYP3A4 TDI by a rapid convenient way is of great importance to any new drug discovery effort. Here, we report the development of in silico classification models for prediction of potential CYP3A4 time-dependent inhibitors. On the basis of the CYP3A4 TDI data set that we manually collected from literature and databases, both conventional machine learning and deep learning models were constructed. The comparisons of different sampling strategies, molecular representations, and machine-learning algorithms showed the benefits of a balanced data set and the deep-learning model featured by GraphConv. The generalization ability of the best model was tested by screening an external data set, and the prediction results were validated by biological experiments. In addition, several structural alerts that are relevant to CYP3A4 time-dependent inhibitors were identified via information gain and frequency analysis. We anticipate that our effort would be useful for identification of potential CYP3A4 time-dependent inhibitors in drug discovery and design.

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“…Two tetrahydroisoquinoline derivatives have also been shown to display effectiveness in animal models (366,367)…”

Section: Pharmacological Manipulation Of Ca V 2 Channelsmentioning

confidence: 99%

“…Two tetrahydroisoquinoline derivatives have also been shown to display effectiveness in animal models ( 366 , 367 ) but again clinical efficacy has not yet been demonstrated.…”

Section: Voltage-gated Ca 2+ Channelsmentioning

confidence: 99%

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

Alles

Smith

2021

Front. Pain Res.

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The persistence of increased excitability and spontaneous activity in injured peripheral neurons is imperative for the development and persistence of many forms of neuropathic pain. This aberrant activity involves increased activity and/or expression of voltage-gated Na+ and Ca2+ channels and hyperpolarization activated cyclic nucleotide gated (HCN) channels as well as decreased function of K+ channels. Because they display limited central side effects, peripherally restricted Na+ and Ca2+ channel blockers and K+ channel activators offer potential therapeutic approaches to pain management. This review outlines the current status and future therapeutic promise of peripherally acting channel modulators. Selective blockers of Nav1.3, Nav1.7, Nav1.8, Cav3.2, and HCN2 and activators of Kv7.2 abrogate signs of neuropathic pain in animal models. Unfortunately, their performance in the clinic has been disappointing; some substances fail to meet therapeutic end points whereas others produce dose-limiting side effects. Despite this, peripheral voltage-gated cation channels retain their promise as therapeutic targets. The way forward may include (i) further structural refinement of K+ channel activators such as retigabine and ASP0819 to improve selectivity and limit toxicity; use or modification of Na+ channel blockers such as vixotrigine, PF-05089771, A803467, PF-01247324, VX-150 or arachnid toxins such as Tap1a; the use of Ca2+ channel blockers such as TTA-P2, TTA-A2, Z 944, ACT709478, and CNCB-2; (ii) improving methods for assessing “pain” as opposed to nociception in rodent models; (iii) recognizing sex differences in pain etiology; (iv) tailoring of therapeutic approaches to meet the symptoms and etiology of pain in individual patients via quantitative sensory testing and other personalized medicine approaches; (v) targeting genetic and biochemical mechanisms controlling channel expression using anti-NGF antibodies such as tanezumab or re-purposed drugs such as vorinostat, a histone methyltransferase inhibitor used in the management of T-cell lymphoma, or cercosporamide a MNK 1/2 inhibitor used in treatment of rheumatoid arthritis; (vi) combination therapy using drugs that are selective for different channel types or regulatory processes; (vii) directing preclinical validation work toward the use of human or human-derived tissue samples; and (viii) application of molecular biological approaches such as clustered regularly interspaced short palindromic repeats (CRISPR) technology.

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Discovery of a 1-isopropyltetrahydroisoquinoline derivative as an orally active N-type calcium channel blocker for neuropathic pain

Cited by 9 publications

References 39 publications

Synthesis, crystal structure and docking studies of tetracyclic 10-iodo-1,2-dihydroisoquinolino[2,1-b][1,2,4]benzothiadiazine 12,12-dioxide and its precursors

Synthesis, crystal structure and docking studies of tetracyclic 10-iodo-1,2-dihydroisoquinolino[2,1-b][1,2,4]benzothiadiazine 12,12-dioxide and its precursors

Development of In Silico Models for Predicting Potential Time-Dependent Inhibitors of Cytochrome P450 3A4

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

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