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Relationship between structure and efficacy at central benzodiazepine receptors for a series of imidazopyrimidines and imidazoquinolines
Author(s) -
Gardner Colin R.,
Budhram Paula,
Deacon Robert M. J.,
Thomson T. Andrew
Publication year - 1991
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430220403
Subject(s) - inverse agonist , chemistry , antagonist , anticonvulsant , pharmacology , benzodiazepine , anxiolytic , agonist , receptor , partial agonist , stereochemistry , psychology , neuroscience , biochemistry , medicine , epilepsy
The efficacy of a series of novel imidazoquinolines and imidazopyrimidines at benzodiazepine (BDZ) receptors was assessed using in vivo models: food‐motivated conflict in rats, stress‐induced ultrasounds in rat pups, leptazol seizures in mice, and suprahyoid muscle twitching in urethane‐anaesthetized rats. Compounds showing activities similar to classical BDZs (anxiolytic, anticonvulsant, and central nervous system (CNS) depressant activities, as well as depression of twitching) have been classified as strong agonists while those showing reduced CNS depressant effects, or reduced anticonvulsant effects with an antagonist profile in twitching, have been classified as moderate and weak partial agonists, respectively. Compounds were regarded as weak or strong inverse agonists according to their abilities to potentiate both seizures and twitching at doses which antagonize full BDZ agonists in the models of anxiety. Modification of two regions of these molecules caused changes in their efficacies. Agonist efficacy following modification to position 2 gave the ranking: oxadiazole > benzoyl > > cyclopropyl ketone ≧ thiazole with the latter compounds becoming inverse agonists in some cases, depending on other changes to the structure. The imidazoquinolines were stronger agonists than the imidazopyrimidines. As the 5,6‐substitutions on the imidazopyrimidines were reduced, compounds possessed less agonism and more inverse agonism, giving the agonism ranking 5‐methyl, 6‐allyl > 5‐methyl, 6‐ethyl > 5,6‐tetramethylene > 5‐ethyl,6‐H ≧ 5‐methyl,6‐H. Combination of the effects of modification of these two regions of the molecules has yielded a scheme which predicts the efficacy of individual members of the series. This scheme has been used to design other molecules with specific efficacies for BDZ receptors in this and other chemical series.