Diazepam and desmethyldiazepam differ in their affinities and efficacies at ‘central’ and ‘peripheral’ benzodiazepine receptors

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Abstract
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 > diazepam > desmethyldiazepam > clonazepam > 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.