Reverse stereoselectivity of opiate and benzodiazepine receptors for the opioid benzodiazepine tifluadom

Kley, Hartmut; Scheidemantel, Ursula; Bering, Birgit; Müller, Wernér E.G.

doi:10.1016/0014-2999(83)90095-x

Cited by 23 publications

(6 citation statements)

References 3 publications

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“…From the above results it is postulated that (+)-tifluadom interacts pre dominantly with the opioid kappa receptor, while (-)-tifluadom triggers benzodiazepine receptor-related EEG changes. These find ings corroborate those studies in which the (+)-isomer binds equally well with opioid and benzodiazepine receptors [22], The ef fects of tifluadom on SEP, i.e.. the transmis sion and modulation of stimuli in sensory integrating centers of the CNS, are typical for kappa opioids. Similar to bremazocine [2], (+)-tifluadom induces a dose-related in crease of latency of the late (> 50 ms) evoked potential.…”

Section: Discussionsupporting

confidence: 79%

The Benzodiazepine (+)-Tifluadom (KC-6128), but Not Its Optical Isomer (KC-5911) Induces Opioid kappa Receptor-Related EEG Power Spectra and Evoked Potential Changes

Freye¹,

Boeck²,

Schaal³

et al. 1986

Pharmacology

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Tifluadom, a benzodiazepine with purported opioid receptor-related analgesic properties, was studied in regard to its acute effects on power spectra of the EEG to demonstrate vigilance changes. Additionally, somatosensory-evoked potentials (SEP) were derived to evaluate its effect on the propagation of impulses in sensory nerve fibers. In order to demonstrate stereospecificity, the two enantiomers of tifluadom (KC-5911 and KC-6128) were given in graded doses (20, 40, 80, 160 µg/kg i.v.) to awake, unrestrained and trained dogs at 10-min intervals. KC-6128, but not its optical counterpart KC-5911, induced synchronization of the EEG at 20 µg/kg with an increase of power (pW) in the delta (1–4 Hz; + 300%), theta (4–8 Hz; +450%), and alpha (8–13 Hz +90%) bands. This was accompanied by a reduction of power in the fast beta domain (13–30 Hz; –95%). Vigilance changes were reflected in the beta/delta quotient which dropped from 3.7 (control) to 0.8 (20 µg/kg) and to 0.3 (40 µg/kg). A further increase in the dose resulted in saturation. At the highest dose (160 µg/kg) there was an additional reduction of the beta/delta quotient to 0.1. In order to unmask the receptor population, possibly mediating the observed changes, a benzodiazepine antagonist and opioid antagonists were given. Ro 15-1788 (240 µg/kg) had no effect and naloxone (20 µg/kg) induced a short term (5 min) arousal. Only the kappa antagonist Mr 2266 (20 µg/kg) induced a reversal of the beta/delta quotient back to 5.5. KC-5911 induced an insignificant drop in the beta/delta quotient which was reversed by Ro 15-1788. In somatosensory-evoked potentials, only KC-6128 induced a dose-related suppression of amplitude and an increase of latency of the late N₁₀₀ potential by -76 and +36%, which peaked at 160 und 80 µg/kg, respectively. Mr 2266 reversed the suppression of amplitude and the increase of latency back to control. Thus, slowing of EEG activity, increase of latency and suppression of amplitude of the N₁₀₀peak in the SEP induced by KC-6128 seems to be mediated by the opioid kappa receptor. KC-5911-induced EEG changes are related to benzodiazepine receptor interaction.

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Section: Discussionsupporting

confidence: 79%

The Benzodiazepine (+)-Tifluadom (KC-6128), but Not Its Optical Isomer (KC-5911) Induces Opioid kappa Receptor-Related EEG Power Spectra and Evoked Potential Changes

Freye¹,

Boeck²,

Schaal³

et al. 1986

Pharmacology

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“…Tifluadom ( 5 ) is a 2-[(acylamino)methyl]-1,4-benzodiazepine with negligible effects upon classical central benzodiazepine receptors, which also shows high affinity for the κ-opioid receptor and causes antinociception in several animal models . Additional activities noted with tifluadom include locomotor disturbances, diuresis, anti-inflammatory activity, and effects on food consumption: all of these effects are thought to be associated with activity at κ-opioid receptor.…”

Section: Introductionmentioning

confidence: 99%

“…15 However, of these receptor subtypes, only one, with the characteristics of a κ 1 -receptor [specific ligand, the arylacetamide U-69,593 (2b) 16 ], has been isolated, cloned, and expressed from a variety of species [17][18][19] including man 20 and, like the other opioid receptors belongs to the G-protein coupled receptors (GPCRs) superfamily, appears to be a classical seventransmembrane receptor. 21 Tifluadom (5) 22 is a 2-[(acylamino)methyl]-1,4-benzodiazepine with negligible effects upon classical central benzodiazepine receptors, 23 which also shows high affinity for the κ-opioid receptor 24 and causes antinociception in several animal models. 25 Additional activities noted with tifluadom include locomotor disturbances, 26 diuresis, 27 anti-inflammatory activity, 28 and effects on food consumption: 29 all of these effects are thought to be associated with activity at κ-opioid receptor.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Biological Evaluation, and Quantitative Receptor Docking Simulations of 2-[(Acylamino)ethyl]-1,4-benzodiazepines as Novel Tifluadom-like Ligands with High Affinity and Selectivity for κ-Opioid Receptors

Cappelli¹,

Anzini²,

Vomero³

et al. 1996

J. Med. Chem.

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The synthesis and biological evaluation of a series of 2-substituted 5-phenyl-1,4-benzodiazepines, structurally related to tifluadom (5), the only benzodiazepine that acts simultaneously as a kappa-opioid agonist and a cholecystokinin-A (CCK-A) antagonist, are reported. The radioligand binding models used in these studies were [(125)I](BH)-CCK-8 in rat pancreas (CCK-A), [(3)H]-(MENLE(28,31))-cck-8 in guinea pig cerebral cortex (CCK-B), and [(3)H]U-69593 (kappa(1)), [(3)H]DAMGO (mu), and [(3)H]DADLE (delta) in guinea pig brain. All the title compounds were devoid of significant affinity for both CCK-A and CCK-B receptors, while some of them bound with nanomolar affinity and high selectivity for kappa-opioid receptors. In particular, the 2-thienyl derivative 7A(X = H) with a K(i) = 0.50 nM represents a clear improvement with respect to tifluadom, showing a comparable potency but higher selectivity. The application of computational simulations and linear regression analysis techniques to the complexes between guinea pig kappa (kappa(1))-receptor and the title compounds allowed the identification of the structural determinants for recognition and quantitative elucidation of the structure-affinity relationships in this class of receptors.

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“…Conversely, the affinity for the benzodiazepine receptor is mediated mainly by the (R) enantiomer. [9][10][11] To date, 2a and 3a-e have been tested as racemic compounds, but the enantiomers' different specificity of action could be expected due to the results shown for (S)-and …”

mentioning

confidence: 84%

Enantiomers of 2‐[(Acylamino)ethyl]‐1,4‐benzodiazepines, Potent ligands of κ‐opioid receptor: Chiral chromatographic resolution, configurational assignment, and biological activity

et al. 2001

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Compounds 2a and 3a-e are racemic 2-[(acylamino)ethyl]-1,4-benzodiazepines, tifluadom analogs, with high affinity and selectivity towards the kappa-opioid receptor. We describe the enantiomeric separation of all compounds through liquid chromatography with chiral stationary phases, as well as the resolution of the enantiomers of the most interesting compounds, 2a and 3a, by the semipreparative column Chiralpak AD. The configuration of the resolved enantiomers was investigated: the comparative study of CD and (1)H NMR spectra shows that compounds (-)-2a and (-)-3a have the same absolute configuration of (+)-(S)-tifluadom. A study on the stereoselective interaction with opiate receptors is reported.

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Reverse stereoselectivity of opiate and benzodiazepine receptors for the opioid benzodiazepine tifluadom

Cited by 23 publications

References 3 publications

The Benzodiazepine (+)-Tifluadom (KC-6128), but Not Its Optical Isomer (KC-5911) Induces Opioid kappa Receptor-Related EEG Power Spectra and Evoked Potential Changes

The Benzodiazepine (+)-Tifluadom (KC-6128), but Not Its Optical Isomer (KC-5911) Induces Opioid kappa Receptor-Related EEG Power Spectra and Evoked Potential Changes

Synthesis, Biological Evaluation, and Quantitative Receptor Docking Simulations of 2-[(Acylamino)ethyl]-1,4-benzodiazepines as Novel Tifluadom-like Ligands with High Affinity and Selectivity for κ-Opioid Receptors

Enantiomers of 2‐[(Acylamino)ethyl]‐1,4‐benzodiazepines, Potent ligands of κ‐opioid receptor: Chiral chromatographic resolution, configurational assignment, and biological activity

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