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A 7‐phenyl substituted triazolopyridazine has inverse agonist activity at the benzodiazepine receptor site
Author(s) -
Biziere K.,
Bourguig J.J.,
Chambon J.P.,
Heaulme M.,
Perio A.,
Tebib S.,
Wermuth C.G.
Publication year - 1987
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1987.tb16839.x
Subject(s) - inverse agonist , anxiogenic , benzodiazepine , pharmacology , flunitrazepam , diazepam , chemistry , convulsant , anticonvulsant , agonist , in vivo , gabaa receptor , pyridazine , oxotremorine , receptor , stereochemistry , anxiolytic , medicine , epilepsy , biochemistry , biology , microbiology and biotechnology , psychiatry
1 To investigate further the structural requirements for benzodiazepine (BZD) receptor ligands, we synthesized SR95195, [7‐phenyl‐3‐methyl‐1,2,4‐triazolo‐(4,3‐b) pyridazine], a positional isomer of the 6‐phenyl‐triazolo‐pyridazines, which were the first non‐BZD derivatives to exhibit high affinity for the BZD receptor and BZD‐like activity in vivo.2 In vitro , SR95195 displaced specifically bound [ 3 H]‐flunitrazepam from rat cerebellar and hippocampal membranes with respective IC 50 values of 4 and 8 μ m . 3 In vivo , SR95195 lacked BZD‐like activity. At high doses SR95195 induced clonic seizures in mice (threshold convulsant dose: 150 mg kg −1 ; CD 50 : 160 mg kg −1 i.p.) which were antagonized by Ro 15–1788. At non‐convulsant doses (25 mg kg −1 i.p. and 100 mg kg −1 i.p.). SR95195 significantly decreased punished responding in an operant conflict procedure in the rat, suggesting SR95195 has intrinsic anxiogenic activity. 4 SR95195, in mice, reversed the anticonvulsant and myorelaxant actions of diazepam 3 mg kg −1 , orally (respective ED 50 values: 45 mg kg −1 i.p. and 44 mg kg −1 i.p.). In an operant‐conflict test in rats, SR95195 at non‐anxiogenic doses, antagonized the disinhibitory action of diazepam 4 mg kg −1 , i.p. (ED 50 : 8.6 mg kg −1 , i.p.), but not that of pentobarbitone 15 mg kg −1 , i.p. 5 It is concluded that SR95195 has the pharmacological profile of an inverse BZD agonist and that displacing the phenyl from the 6‐ to the 7‐position in the triazolopyridazine series causes a shift from agonist to inverse agonist type activity at the BZD receptor site.