Diazepam and desmethyldiazepam differ in their affinities and efficacies at 'central' and 'peripheral' benzodiazepine receptors.
The in-vitro binding characteristics of three different ligands ([ 3H]Ro 15-1788, [3H]Ro 5-4864 and [3H]flunitrazepam) and the structural requirements for binding to 'central' and 'peripheral' benzodiazepine receptors have been evaluated in rat cerebral cortex, cerebellum and adrenal glands. [3H]Ro 15-1788 binding was detectable only in the brain. Clonazepam was the most potent inhibitor followed by diazepam and desmethyldiazepam, which showed the same affinity, and by premazepam; Ro 5-4864 did not show appreciable affinity. The same pattern was seen for [3H] flunitrazepam binding in brain areas while in adrenal gland the inhibition pattern was exactly superimposable on that with [3H]Ro 5-4864 in all the areas considered (Ro 5-4864 greater than diazepam greater than desmethyldiazepam greater than clonazepam greater than premazepam). These data confirm and extend previous reports. A methyl group in position 1 enhances the affinity for peripheral benzodiazepine binding sites which are labelled in the adrenal gland by [3H]Ro 5-4864 and [3H]flunitrazepam; in brain areas, [3H]flunitrazepam, like [3H]Ro 15-1788, selectively labels central binding sites. Methylation in position 1 did not change the affinity for these sites. Desmethyldiazepam is less active than diazepam as an anticonvulsant and in other tests. In-vivo experiments were therefore carried out to assess the 'intrinsic activity' of desmethyldiazepam: it appeared that this compound acts as a partial agonist at central benzodiazepine receptors.
D000311:Adrenal Glands / Q000378:metabolism*; D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003975:Diazepam / Q000031:analogs & derivatives* / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D003708:Nordazepam / Q000378:metabolism*; D051381:Rats; D011963:Receptors, GABA-A / Q000145:classification / Q000378:metabolism*
D011963:Receptors, GABA-A; D001569:Benzodiazepines; D003708:Nordazepam; D003975:Diazepam