Benzodiazepin receptor affinity

Factors that indicate a causal association between triazolam and adverse behavioral reactions include corroborating case reports and sleep laboratory studies in the literature, reports of reactions in otherwise normal persons, acute onset and temporal relationship to reactions with initial dose, spontaneous recoveries and return to normalcy with drug discontinuation, and occurrences of positive rechallenge. Also, the high benzodiazepine receptor affinity with triazolam has been postulated as a possible biological mechanism. 

Phenyl-l,2,4-triazolo[l,5-c][l,3]benzoxazin-5-one 743, which exhibits benzodiazepine receptor affinity, has been prepared by cyclizing the 3-phenyl-5-(2-hydroxy-phenyl)- ,2,4-triazole 742 [535]. 

In this exercise, we compare MLR and SVMR QSAR models for the benzodiazepine receptor affinity of 52 2-aryl(heteroaryl)-2,5-dihydropyrazo-lo[4,3-c]quinolin-3-(3H)-ones (Figure 53). Both models were developed with five structural descriptors, namely the Hammett electronic parameter Qr, the molar refractivity MRrs, the Sterimol parameter Lr<4<, an indicator variable 7 (1 or 0) for 7-substituted compounds, and the Sterimol parameter The MLR model has a calibration correlation coefficient of 0.798 and fairly good prediction ability ... 

Kavvadias D, Monschein VS, Riederer P, Schreier P. Constituents of sage (Salvia officinalis) with in vitro affinity to human brain benzodiazepine receptor. Planta Med 2003 69 113-117. 

A series of 2-phenyl [ 1,2,3 triazolo[l,2-tf][l,2,4]bcnzotriazin-l,5(6//)-diones display submicromolar/nanomolar potency at the central benzodiazepine receptor. The most potent compound 687 (Kj= 2.8 nM) with enhanced affinity is a full agonist at al and aZ receptor subtypes, and has an antagonist efficacy at a5 receptors <2005JME2936>. 

From the examination of structure-activity relationships, it has been concluded that a phenyl moiety at C-6 as well as a 4-hydroxypiperidine side-chain attached to C-3 of the pyridazine system is essential for anticonvulsant activity in this class of compounds [184], Compounds (54) and (55) have been found to have similar anticonvulsant profiles in animals (mice, rats and baboons) [165, and literature cited therein] and to represent potent broad-spectrum antiepileptic drugs. Their potency with regard to antagonizing seizures (induced by electro-shock or various chemicals) has been compared with standard anticonvulsants like carbamazepine and phenobarbitone [185, 186], A quantitative electroencephalographic analysis of (55) has been published [187]. From in vitro studies it has been concluded that the anticonvulsant activities of these compounds are not mediated by an enhancement of GABAergic transmission or by an interaction with benzodiazepine receptor sites [ 165,186,187], On the other hand, in vivo experiments showed that (54), at anticonvulsant doses, increases the affinity of flunitrazepam for its central receptor site [ 186], Investigations of (54) and (55) in a behavioural test predictive of antianxiety activity revealed a marked difference in the pharmacological profiles of these structurally closely related compounds the dichloro compound SR 41378 (55) has also been found to possess anxiolytic (anticonflict) properties [165],... 

Perhaps the most studied constituent of passionflower is the flavonoid chrysin. Chiysin was isolated from P. coeruiea, a species closely related to P. incarnata. It binds to benzodiazepine receptors with micromolar affinity (Ki = 3 pM) and competes for binding with the benzodiazepine flunitrazepam (Medina et al. 1990). Behavioral assays (see below) suggest that chrysin acts as a partial agonist at central benzodiazepine receptors (Wolfman et al. 1994). 

Nielsen M, Frokjaer S, Braestrup C. (1988). High affinity of the naturally-occurring biflavonoid, amentoflavon, to brain benzodiazepine receptors in vitro. Biochem Pharmacol. 37(17) 3285-87. 

Zopiclone is widely used as a sedative-hypnotic. It is metabolized to an inactive N-desmethylated derivative and an active N-oxide compound, both of which contain chiral centres. S-Zopiclone has a 50-fold higher affinity for the benzodiazepine receptor site than the R-enantiomer. This could be therapeutically important, particularly if the formation and the urinary excretion of the active metabolite benefits the S-isomer, which appears to be the case. As the half-life of the R-enantiomer is longer than that of the S-form, it would seem advantageous to use the R-isomer in order to avoid the possibility of daytime sedation and hangover effects which commonly occur with long-acting benzodiazepine receptor agonists. 

Benzodiazepine antagonists, such as flumazenil, possess affinity for benzodiazepine receptors, but they lack intrinsic activity. Flumazenil is an effective antidote in the treatment of benzodiazepine overdosage or can be used postoperatively to arouse patients sedated with a benzodiazepine. 

A series of imidazo[l,5-a]quinoxaline amides, carbamates, and ureas which have high affinity for the y-aminobutyric acid A/benzodiazepine receptor complex was developed. Compounds within this class have varying activities ranging from antagonists to full agonists. However, most analogs were found to be partial agonists as indicated by [ S]TBPS and Cl current ratios. Many of these... 

Several studies have suggested increased sensitivity of older persons to effects of benzodiazepines (Table 3). For example, midazolam, widely used for rapid sedation for procedures, requires lower doses to reach defined end points of sedation that is attributable to a 59% reduction in the EC50 (the concentration that produces 50% of the maximum effect) and not to changes in pharmacokinetics, as shown in Fig. 3. The reasons for this increased sensitivity are not known. Animal studies have not shown any difference in brain benzodiazepine receptor density or affinity or effects on the associated chloride channel function with ageing. In any event, benzodiazepine doses should be reduced in older patients. 

Pyrrolo[3,4-, ]pyridine derivatives, 147, have been prepared for comparison to the activity of alpidem, an anxiolytic imidazopyridine <1996JME4275>. The reduced derivative shows a significant affinity for the central benzodiazepine receptor. In contrast, the a,/3-unsaturated derivative shows significant affinity for the peripheral benzodiazepine receptor. 

The mechanism of action of midazolam though not clearly understood is probably similar to other benzodiazepines i.e. through interference with GABA reuptake. It has a relatively high affinity for benzodiazepine receptors. 

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