Recent Structure Activity Relationship Studies of 1,4-Benzodiazepines (original) (raw)
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Journal of Pharmaceutical Sciences, 1993
0 Certain new (1-15) or previously described (16-25) 1,2,3triazole derivatives, characterized by a C-benzoyl substituent, were synthesized and tested for their ability to displace f'H]flunitrazepam from bovine brain membrane. Compounds l l a and Sa, bearing neutral and lipophilic substituents (phenethyl and cyclohexyl, respectively) showed the higher activity. The 5-benzoyl isomer 11 b presented a lower activity, equivalent to that of the triazole acetic derivative 23, which is 4-benzyl substituted. Generally, the carboxymethyl radical in the 1 -position of the triazole ring decreased the activity, probably because of intramolecular hydrogen bonding with the carbonyl function of the benzoyl substituent. The N-1 unsubstituted triazole derivatives 24 and 25 were ineffective; this result is in disagreement with our previous observations. Probably these molecules interact with the receptor site by a hydrogen bonding acceptor group and by a bulky and lipophilic portion or a hydrogen bonding donor function that is appropriately arranged.
Specific inhibition of binding to benzodiazepine receptors by 1, 2, 3-triazole derivatives
Journal of Pharmaceutical Sciences, 1992
0 Certain 1,2,34riazole derivatives were prepared and tested for their ability to displace [3H]diazepam that was bound to bovine brain membrane protein. All the tested compounds are essentially lacking in this ability, except for 8.1, which inhibited binding of [,H]diazepam in 50% of the trials at 2.5 f l . The structure of 8.1, with a 1,2,3-triazole ring with acidic properties, supports the hypothesis proposed for binding to the benzodiazepine receptor site. Comparison of 8.1 with 1,2,3-triazole derivatives bearing a bicyclic substituent in position 1 of the heterocyclic ring suggests that a high steric hindrance increases the affinity of a compound for the benzodiazepine receptor.
Journal of Molecular Structure-theochem, 1999
The series of compounds investigated includes 23 benzodiazepine derivatives, some of which demonstrate anxiolytic, anticonvulsant and sedative-hypnotic properties. The series was partitioned into two classes of active and inactive compounds. Preliminary calculations of the electronic and geometry parameters were carried out to form the so-called electron-topologic matrices of contiguity (ETMC) for each compound in the series. By comparing the matrices, the molecular fragment responsible for the desired activity has been found in all ETMC of the active compounds as a common submatrix, and is called ''the activity feature''. A submatrix of the molecular fragment that is the feature of inactivity has been revealed, too. The properties of the two features have been studied and used as rules to predict the desired activity in a series of new compounds. ᭧ 1999 Elsevier Science B.V. All rights reserved.
2002
The synthesis of 3-(2-furyl)- and 3-(3-furyl)-8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides is reported. The binding affinities at the central Benzodiazepine Receptor (BZR) and the muscle relaxant, anticonvulsant and anxiolytic activities of new furyl derivatives are compared to those of the 3-heteroarylderivatives, BZR ligands previously reported by us. The results confirm the stringent spatial requisites of the lipophilic pocket that accommodates the 3-substituent, which seems to influence both the binding and intrinsic activity of this new class of ligands.
Journal of Medicinal Chemistry, 1985
0 Certain 1,2,3-triazole derivatives were prepared and tested for their ability to displace [3H]diazepam from bovine brain membranes. From these compounds, the quinolyltriazole derivatives (14, 15, 16, 17) were clearly the most potent, while the naphthyl-and the naphthyridyltriazoles were considerably less active. The pnitrophenyl derivative (1 5) was the compound that bound with the highest affinity within the quinolyltriazole compounds class. The replacement of the pnitrophenyl group with other substituents greatly decreased the binding activity. From a Lineweaver-Burk analysis of 11, it appears that the inhibition is competitive.
Journal of Medicinal Chemistry, 1999
The synthesis of new 3-heteroaryl-8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides and their binding activities at the central benzodiazepine receptor (BZR) are reported. The derivatives substituted at the 3-position with electron-rich five-membered rings, such as pyrrole 11, 2-thiophene 13c, or 3-thiophene 13d, showed good affinity values for BZR. In in vivo tests the 3-(thien-3-yl)-8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide (13d) showed selective anticonvulsant activity. a This compound is a 5-deoxy derivative: 3-(thien-2-yl)-8-chloropyrazolo[5,1-c][1,2,4]benzotriazine. Scheme 1 a a (a) DMF-DMA or DMA-DMA; (b) hydrazine hydrate; (c) CH3I; (d) acetic acid/H2O; (e) NH2OH‚HCl.
EXCLI journal, 2017
A new series of 4-chloro-N-(2-(substitutedphenyl)-4-oxothiazolidin-3-yl)-2-phenoxybenzamide derivatives were designed, synthesized and biologically evaluated as anticonvulsant agents. The designed compounds have the main essential functional groups for binding to the benzodiazepine receptors and 4-thiazolidinone ring as an anticonvulsant pharmacophore. Some of the new synthesized compounds showed considerable anticonvulsant activity in electroshock and pentylenetetrazole-induced lethal convulsion tests. Compound 5i, 4-chloro-N-(2-(4-methoxyphenyl)-4-oxothiazolidin-3-yl)-2-phenoxybenzamide, with the best activity was selected for evaluation of other benzodiazepine pharmacological effects. This compound induced significant sedative-hypnotic activity. However, it does not impair the learning and memory in the experimental condition. Flumazenil was able to antagonize the sedative-hypnotic and anticonvulsant effects of compound 5i indicating that benzodiazepine receptors are highly invol...
Bioorganic & Medicinal Chemistry, 1993
A series of 2-aryl-2,5-dihydropyridazino [4,3-b]indol-3(3H)-ones 5 were prepared and evaluated for their ability to inhibit radioligand binding to BZR, and to prevent sound and pentylenetetrazole (PlZ) induced seizures in mice. The biological and pharmacological results are discussed in the light of some recently proposed pharmacophore models and compared through molecular orbital and molecular modeling studies to those obtained from the close pyrazoloquinoline analogs 6. 431 438 0 / di= I i o-\ NH ii ,Cl -1 N---N/ N-N; 3 a-d 4 a-d 5 a-d X:a=H;b=OCH3;c=Cl;d=Br Scheme I. Reagents: (i) Triphosgene NEt,, anhydrous dioxane, reflux; (ii) (COOC2H5)2CHmNa+, r.t.; (iii) X-PhNHNHrHCl, EtOHM20, reflux; (iv) NaOH, EtOH, r&ux; (v) H*rr.t.; <vi) A, 350 "C.
ChemInform, 2012
a b s t r a c t A new series of 6,7-dihydro-thiazolo[3,2-a][1,3]diazepines (9e12), benzo[d]thiazolo[5,2-a][12,6]diazepines (19e21) and benzo[d]oxazolo[5,2-a][12,6]diazepine (24) analogues were synthesized and evaluated for their anticonvulsant activity. Compounds (E)-2-bromo-6,7-dihydro-thiazolo[3,2-a][1,3] diazepine-8(5H)-thione (12), 3-chloro-benzo[d]thiazolo[5,2-a][12,6]diazepin-10-one (20), and 4-chlorobenzo[d]oxazolo[5,2-a][12,6] diazepin-10-one (24) showed 100% protection against PTZ-and bicuculline-induced seizures; 70%, 33%, 70% protection against MES-induced tonic extension; and 70%, 66%, 100% protection against picrotoxin-induced convulsions, respectively. Compounds 12, 20, and 24 proved to act as GABA A receptor agonists, with ED 50 values of 252, 380, 251 mg/kg; TD 50 values of 398, 417, 355 mg/kg; PI values of 1.58, 1.09, 1.41; LD 50 values of 380, 617, 537 mg/kg and TI values of 1.51, 1.62, 2.14, respectively.
Bioorganic & Medicinal Chemistry, 2014
The new series of 5-(2-phenoxybenzyl)-4H-1,2,4-triazoles, possessing C-3 thio, alkylthio and ethoxy substituents, and 2-amino-5-(2-phenoxybenzyl)-1,3,4-oxadiazoles were designed and synthesized as novel benzodiazepine analogues. Most of them revealed similar to superior binding affinity to the GABAA/benzodiazepine receptor complex, relative to diazepam as the reference drug. Among them, 5-(4-chloro-2-(2-fluorophenoxy)benzyl)-3-benzylthio-4H-1,2,4-triazole (8l) showed the highest affinity (IC₅₀=0.892 nM) relative to diazepam (IC₅₀=2.857 nM) and also showed the most increase in pentylenetetrazole-induced seizure threshold relative to diazepam as the reference drug.