Barbiturates general structure

The barbiturates are derivatives of barbituric acid and have the general structure given below. The nitrogen atom at position 1 may be methylated. Substitution of sulphur for oxygen at position 2 gives the thiobarbiturates. 

Benzodiazepines, which have the generalized structure shown as 3, were introduced to replace the barbiturates as tranquilizers, anxiolytics, anticonvulsants and muscle relaxants. All those encountered in the forensic science context have been diverted from licit sources. The majority appear as tablets and capsules, although powders and injectable solutions may also be encountered. 

In general, structural changes in the barbiturate series (see Chapter I4 that favor partitioning into the lipid tissue stores decrease duration of action but increase central nervous system (CNS) depres.sion. Conversely, the barbiturates with the slowest onset of action and longest duration of action contain the more polar side chains. This latter group of barbiturates both enters and leaves the CN.S more slowly than the more lipophilic thiopental. 

Several approaches [12, 13] have been published for the fluorometric determination of barbiturates. A general structure for the enol tautomer of most common barbiturates is... 

The structure of barbituric acid was the subject of disagreement for many years, but since 195 2 (52BSB44) the trioxo formulation (57 R = H) has been accepted generally, along with the fact that barbituric acid loses a proton, first from carbon (anion) and subsequently from nitrogen (dianion). Barbital (5,5-diethylbarbituric acid) adopts a similar trioxo form (57 R = Et) (69AX(B)1978). 

Despite the work of Overton and Meyer, it was to be many years before structure-activity relationships were explored further. In 1939 Ferguson [10] postulated that the toxic dose of a chemical is a constant fraction of its aqueous solubility hence toxicity should increase as aqueous solubility decreases. Because aqueous solubility and oil-water partition coefficient are inversely related, it follows that toxicity should increase with partition coefficient. Although this has been found to be true up to a point, it does not continue ad infinitum. Toxicity (and indeed, any biological response) generally increases initially with partition coefficient, but then tends to fall again. This can be explained simply as a reluctance of very hydrophobic chemicals to leave a lipid phase and enter the next aqueous biophase [11]. An example of this is shown by a QSAR that models toxicity of barbiturates to the mouse [12] ... 

Since general anesthetics are related to a variety of classes of chemical compounds, there is no general pattern that exists between their chemical structure and their activity. Particular patterns only exist for different groups of compounds (barbiturates, benzodiazepines, etc.). 

The general pharmacology of the barbiturates is discussed in Chapter 22. Thiopental is a barbiturate commonly used for induction of anesthesia. Thiamylal is structurally almost identical to thiopental and has the same pharmacokinetic and pharmacodynamic profile. 

Benzodiazepines are a family of compounds that share the same basic chemical structure and pharmacological effects. Although the more famous members of this family are associated with treating anxiety (e.g., diazepam [Valium] see later in this chapter), several benzodiazepines are indicated specifically to promote sleep (Table 6-1). These agents exert hypnotic effects similar to those of nonbenzodiazepines—such as the barbiturates—but benzodiazepines are generally regarded as safer because there is less of a chance for lethal overdose.22 Benzodiazepines, however, are not without their drawbacks, and they can cause resid-... 

When it comes to physicochemical (biological) properties the common structural formulae obscure rather than explain the problem. One of the most convincing examples may be the anaesthetic activity of chemicals. Among general anaesthetics one can identify such diverse chemical families like hydrocarbons, alcohols, ethers, barbiturates, nitrous oxide, steroids, etc. Each one must have anaesthetic activity encoded in its structure but how is it discovered using conventional chemical symbolic The planar or three-dimensional chemical notation can be an obstacle to making a breakthrough in chemistry. 

Several authors have provided insight into the putative MBS receptor based on their structure-activity data. As noted by Unverferth et al. (281), there have been several attempts to postulate a general pharmacophore for the different anticonvulsant classes, all of which are anti-MES in animal studies and are, or have the potential to be, effective in generalized tonic-clonic seizures. These include benzodiazepines (282) barbiturates (283) triazolines (284) semicarbazones (248-261) and enami-nones (286-288), respectively and for different compounds with similar anticonvulsant profiles (289-292). The Unverferth model (Fig. 6.11) provides an excellent representation of the current anticonvulsants phenytoin (1), carbamazepine (2), lamotrigine (11), zonisamide (13), and rufinamide (60). Remace-mide (58) is also included as a possible candidate (Fig. 6.12). 

Figure 8.11 Chemical structure of barbiturates, (a) General chemical structure of barbiturate drugs. Specific chemical structures for (b) barbital (c) secobarbital ...

Depressants may be hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones, weak acids (like the barbiturates), weak bases, or sulphones. They are the selectively toxic agents used in medicine as hypnotics and general anaesthetics. This is the only kind of biological activity in which structure simply does not matter (there is much more about this in Chapter 15). See Section 3.3 for the general function of partition effects in securing selective distribution of drugs. 

In moderate doses, the action of the benzodiazepines is remarkably like that of the barbiturates, but they are more selective because larger doses do not introduce the toxicity to the patient seen in barbiturate medication. Intravenous diazepam can be used in place of thiopental for the induction of general anaesthesia. It has been found that barbiturates act on the picrotoxin receptor in the GABA—receptor complex (Olsen, 1982) and, in this way, synergize the action of GABA. This effect is stereospecific for in pentobarbital it is confined to the (5)-isomer (Huang and Barker, 1980). It would seem that this type of activity plays only a minor part in medication with barbiturates which behave on the whole as structure-independent lipophiles (see p. 622). 

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