Pharmacological profiles in vivo of benzodiazepine receptor ligands

Abstract

Since the discovery of specific binding sites for benzodiazepines in the brain, a range of compounds have been discovered that do not have the benzodiazepine structure but that do interact with the benzodiazepine receptors. Classical benzodiazepines were considered to be agonists at these receptors. Some compounds only possess part of the profile of classical benzodiazepines and antagonise benzodiazepines in those test procedures in which they are totally inactive. Such compounds are regarded as partial agonists. The discovery of methyl and ethyl β‐carboline‐3‐carboxylate opened a new vista in the pharmacology of benzodiazepine receptors. These agents and now several other compounds act on the benzodiazepine receptors to induce effects functionally opposite to those of classical benzodiazepines (proconvulsant and convulsant) and have been called inverse agonists. Both agonists and inverse agonists can be blocked by compounds with affinity for the receptors but little intrinsic activity (antagonists). A recent increase in the number of benzodiazepine receptor ligands with in vivo activities allows comparison of a range of compounds from several different structral groups. Their pharmacological profiles suggest that these compounds all fit onto a continuum of behavioural effects related to activation of benzodiazepine receptors.

Benzodiazepine analogues inhibit arachidonate‐induced aggregation and thromboxane synthesis in human platelets

“…We also used two flavones (ACA6 and MP37) which exhibit inhibitory effects on platelet aggregation (Beretz & Cazenave, 1988 In an attempt to compare these values with the previously published ones (Wang et al, 1980;Le Fur et al, 1983;Benavides et al, 1984) we calculated the corresponding K; from IC50 values (Table 1). We found a slightly lower affinity for both PK 11195, Ro 4864 and diazepam (K.: 39, 299, 551 nm, respectively) than those previously described (K;: 4, 22, 194nm, respectively Gardner (1988 (Figure 3).…”

Effects of Midazolam on the Differentiation of Murine Myeloid Leukemia Cells

“…The phar macological effects of BDZs are mediated by their interaction with several classes of spe cific binding sites (central-type/periphcraltype BDZ receptors; CDR/PBR) [14], The clinically relevant anxiolytic and anticonvul sant effects of BDZ are believed to be me diated through the binding of BDZ to the CBR [15]. Recent studies indicated that BDZ could also mediate a wide range of nonneural effects on peripheral tissues.…”

Benzodiazepine receptor ligands and hepatic encephalopathy: Further unfolding of the GABA story

“…Consequently, antagonists tend to normalize changes in GABAergic tone induced by agonists or inverse agonists (9,10). Thus BZR ligands have a wide spectrum of intrinsic activities and can be classified with respect to their placement on an intrinsic activity continuum (11) (Fig. 1).…”

“…The properties of a pure antagonist would place it at the central point of this spectrum. However, many drugs classified in the central region, which have weak partial agonist or weak partial inverse agonist properties, act predominantly as antagonists (10,11). Thus, although flumazenil has weak partial agonist actions at relatively high concentrations (12), it is classified as an antagonist (9)(10)(11).…”

“…These drugs have chemical structures closely related to that of flumazenil and bind selectively to the BZR. In contrast to flumazenil these ligands have partial inverse agonist actions (10,11). Both of these ligands unequivocally improved the neurobehavioral status of rats with TAA-induced FHF (5).…”