Flumazenil, structure

Figure 11.6 Schematic representation of the GABAa receptor complex. Examples of the many structurally diverse compounds that act at different sites on the receptor (see text for details). Picrotoxinin, the active component of picrotoxin, and TBPS act as non-competitive antagonists. The barbiturates, steroids and anaesthetics are positive allosteric modulators, as are the benzodiazepine site ligands shown, with the exception of DMCM (negative allosteric modulator) and flumazenil (benzodiazepine site antagonist)...

Drugs that stimulate respiration (analeptics) have a place in anaesthetic practice but are not a substitute for mechanical ventilation. They have a direct effect on respiratory drive they do not share a common molecular structure. Respiratory stimulation is generally better achieved by antagonising the depressant effects of the depressant drug, e.g. flumazenil for benzodiazepines naloxone for opioids. 

Although structurally unrelated to the benzodiazepines, these drugs act on the same macromolecular receptor complex but at different sites from the benzodiazepines their effects can be blocked by flumazenil, the receptor antagonist. Those described below are all effective in insomnia, have low propensity for tolerance, rebound insomnia, withdrawal symptoms and abuse potential but there are few data of their effects in long-term studies. 

Figure 8.2. Molecular structures of (a) 6-18F-L-fluorodopa, (b) nC-flumazenil, (c) uC-methylspiperone, (d) uC-L-methionine, (e) nC-raclopride, (f) 18F-fluoromiso-nidazole (Reprinted with the permission of The Cleveland Clinic Center for Medical Art Photography 2009. All Rights Reserved)...

C-flumazenil is commonly labeled at the A7-me 1 11 yl position by N-methylation with 11 C-iodomethane, which is prepared from 11C-C02, and using the freshly prepared Grignard reagent, methylmagnesium bromide (Maziere et al, 1984). The specific activity is very important for this product and therefore is purified by HPLC to give an optimum value between 0.5 and 2Ci/Vmol (18.5-74GI k]/i imol). It remains stable for up to 3 h at room temperature at pH 7.0. The molecular structure of 11C-fumazenil is shown in Fig. 8.2b. 

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