Active structures in the 2-aminoethylbenzimidazoles series

M, Mousseron; Kamenka, Jean-Marc; Stenger, A.

doi:10.1021/jm00310a045

Cited by 9 publications

(5 citation statements)

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“…It has been demonstrated that the Bruylants reaction gives only a single isomer ( cis ) when 4-substituted α-aminonitriles are used as the substrates for the reaction. 17 However, there was an interest in assaying both isomers of 38 as they have been shown to possess a different pharmacological selectivity 18 and could offer an insight into the optimal arrangement of the piperidine ring, aromatic group and 4-cyclohexyl substituent relative to each other for the inhibition of TryR. Therefore, in order to access both isomers, a modification of the published synthetic route outlined in Scheme 4 was employed.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of 1‐(1‐(Benzo[b]thiophen‐2‐yl)cyclohexyl)piperidine (BTCP) Analogues as Inhibitors of Trypanothione Reductase

et al. 2009

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Thirty two analogues of phencyclidine were synthesised and tested as inhibitors of trypanothione reductase (TryR), a potential drug target in trypanosome and leishmania parasites. The lead compound BTCP (1, 1-(1-benzo[b]thiophen-2-yl-cyclohexyl) piperidine) was found to be a competitive inhibitor of the enzyme (Ki=1 μm) and biologically active against bloodstream T. brucei (EC50=10 μm), but with poor selectivity against mammalian MRC5 cells (EC50=29 μm). Analogues with improved enzymatic and biological activity were obtained. The structure–activity relationships of this novel series are discussed.

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Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of 1‐(1‐(Benzo[b]thiophen‐2‐yl)cyclohexyl)piperidine (BTCP) Analogues as Inhibitors of Trypanothione Reductase

et al. 2009

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“…119 Replacement of the ethoxybenzyl group of etonitazene by heterocyclic amines resulted in a substantial loss of antinociceptive activity. 120 Slight activity was detected only in the mouse writhing assay but not in the hot-plate test. The most active substances were 74, 75, and 76 (Figure 11) with respective ED 50 values of 90, 100, and 110 mg/kg sc; in comparison, for pethidine ED 50 = 4 mg/kg and for etonitazene ED 50 = 0.012 μg/kg, both sc.…”

Section: M1 Etonitazene Isotonitazene Protonitazene Metonitazene Clon...mentioning

confidence: 95%

“…Replacement of the ethoxybenzyl group of etonitazene by heterocyclic amines resulted in a substantial loss of antinociceptive activity . Slight activity was detected only in the mouse writhing assay but not in the hot-plate test.…”

Section: Pharmacologymentioning

confidence: 97%

DARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles

Ujváry¹,

Christie

Evans-Brown

et al. 2021

ACS Chem. Neurosci.

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Etonitazene and related 2-benzylbenzimidazoles are potent analgetics invented in the research laboratories of the Swiss pharmaceutical giant CIBA in the late 1950s. Though the unprecedented structure distinguishes this class of compounds from poppy-derived and other synthetic analgetics, a range of studies indicate that these drugs are selective μ opioid receptor agonists possessing morphine-like pharmacotoxicological properties in animals as well as humans. Several unscheduled members of this synthetically readily accessible class of opioids that are not controlled under the international and national drug control systems have recently emerged on the illicit drug market. Among them, isotonitazene has been implicated in at least 200 fatalities in Europe and North America. None of the 2-benzylbenzimidazole derivatives have been developed into medicines, but etonitazene and some of its derivatives have been used as receptor probes and in addiction behavior studies in animals. The unique structure has inspired research on such benzimidazoles and related benzimidazolones of which “brorphine” made its debut as one of the newest psychoactive substance to emerge on the illicit opioid drug market in mid-2019. This in-depth review provides a historical introduction, an overview on the chemistry, pharmacological profiles, adverse effects, addiction liability, regulatory status, and the impact on chemical neuroscience of the 2-benzylbenzimidazoles. Structurally related benzimidazoles with opioid and/or analgesic properties are also discussed briefly.

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“…The rotarod test has been found to give a good estimate of the pharmacological activity of molecules in the phencyclidine series (10,20). This test is a measure of the disturbance induced by phencyclidines in the forced motor activity of mice.…”

Section: Methodsmentioning

confidence: 99%

Interaction of phencyclidine ("angel dust") with a specific receptor in rat brain membranes.

Vincent¹,

Kartalovski²,

Geneste³

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

203

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I3H]Phencyclidine binds to synaptic membranes from rat brain in a saturable, reversible, and selective fashion, with a dissociation constant Kd of 0.25 jiM and a maximal binding capacity of 2.4 pmol/mg of membrane protein-i.e., 250 pmol/g of brain. The binding activity is concentrated in synaptosomal fractions, is higher in cerebral cortex and corpus striatum than in other parts of the rat brain, and is not detectable in the spinal cord. Only molecules of the phencyclidine series and ketamine are able to bind to the phencyclidine receptor.[3H]Phencyclidine bound to its receptor is not displaced by the classical neurotransmitters or neuromodulators. There is a good correlation between the apparent affinities of a series of phencyclidine analogs for the phencyclidine receptor and the pharmacological activities of these analogs as measured by the rotarod assay.Phencyclidine [N-(l-phenylcyclohexyl)piperidine] was introduced in the late 1950s as an intravenous general anesthetic that was nontoxic and nonflammable and produced minimal cardiorespiratory depression (1, 2). These clinical advantages were unfortunately offset by its prolonged duration of action and psychotomimetic effects (3), properties that have contributed to the emergence of phencyclidine as a major drug of abuse in the United States (4, 5). Phencyclidine produces long-lasting psychosis thought to resemble schizophrenia more than does the psychosis produced by any other psychotomimetic (3). Phencyclidine exaggerates psychopathology. Schizophrenics experience severe thought disorders and behavioral problems as long as 1 month after a single injection. Quiet mental patients become catatonic, and reactive ones become overreactive and restless (6, 7). In this paper we investigate the characterization of the phencyclidine receptor in mammalian brain. The data presented here show that a component present in rat brain membranes binds [3H]phencyclidine specifically and with a fairly high affinity. This component may be the physiologically important receptor that mediates the effects of phencyclidine in the central nervous system. MATERIALS AND METHODSMaterials. Molecules in the phencyclidine series were synthesized as previously described (8). The structures of these drugs are shown in Table 1. [3H]Phencyclidine was prepared on request at New England Nuclear by catalytic reduction at room temperature with tritium gas and purification of the reaction mixture on a silica gel column by high-pressure liquid chromatography. The purity of the product was established by thin-layer chromatography on silica gel in either methanol or 1-butanol/acetic acid/water, 25:4:10 vol/vol/vol. The specific radioactivity of the pure [3H]phencyclidine was 60 Ci/mmol (1 Ci = 3.7 x 1010 becquerels). Trans -r2OMt * Ph, phenyl; Th, 2-thienyl. 4678The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact.

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Active structures in the 2-aminoethylbenzimidazoles series

Cited by 9 publications

References 3 publications

Synthesis and Evaluation of 1‐(1‐(Benzo[b]thiophen‐2‐yl)cyclohexyl)piperidine (BTCP) Analogues as Inhibitors of Trypanothione Reductase

Synthesis and Evaluation of 1‐(1‐(Benzo[b]thiophen‐2‐yl)cyclohexyl)piperidine (BTCP) Analogues as Inhibitors of Trypanothione Reductase

DARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles

Interaction of phencyclidine ("angel dust") with a specific receptor in rat brain membranes.

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