1.5- Benzodiazepines structure

The same approach was readily adaptable to solid-phase synthesis. A small library of unnatural derivatives of 140 was prepared with variation of the configuration and nature of R1 and R4 and with substitution on the benzene ring <2000JC0186>. Three natural alkaloids, Verrucine A, B, and Anacine, were synthesized by a similar pathway and the pyrazino[2,l- ]quinazoline as opposed to the benzodiazepine structure of Anacine was proved <2001JNP1497>. Fiscalin B and other derivatives were prepared by solid-phase synthesis using polyethylene glycol (PEG) resin <2002USP6376667>. 

That the benzodiazepine structure was a prerequisite for the characteristic tranquilizer profile and specific binding at the benzodiazepine receptor was a long-held belief. This has now been shown not to be the case by the discovery of a range of different compounds that bind to the benzodiazepine receptor [Figure 29-2). These include the 3-carbolines (e.g., abecarnil), the triazolo-pyridazines [e.g., GL 218,872), the imidazopyridines (e.g., zolpidem), the cyclopyrrol ones [e.g., suriclone), and the pyrazoloquinolines. 

Kamiya et al. found that 207 (R = H, R = OH) underwent annelation rearrangement in acetyl chloride/DMF to 237. The structure of this latter compound, as well as derivatives of 207 [i.e., R = R = H R = Ac, R = OAc R = Ac, R = OH], were confirmed by X-ray diffraction analysis and were thus incompatible with the earlier benzodiazepine structures assigned to these compounds (73CPB1520) (see Section IV,A,2). 

Until about 1980, it was widely accepted that the benzodiazepine structure was a prerequisite for the anxiolytic profile and for the recognition of and binding to the benzodiazepine receptor. More recently, however, a chemically unrelated drug, the cyclopyrrolone zopiclone, has been shown to be a useful sedative hypnotic with a benzodiazepine-like profile. Other chemical classes of drugs that are also structurally dissimilar to the benzodiazepines (e.g. triazolopyridazines) have also been developed and shown to have anxiolytic activity in man these non-benzodiazepines also act via the benzodiazepine receptor. Thus the term "benzodiazepine receptor ligand" has been introduced to describe all drugs, irrespective of their chemical structure, that act on benzodiazepine receptors and thereby modulate inhibitory transmission in the brain. 

The third group of compounds are the naturally occurring benzodiazepines. Desmethyldiazepam has been isolated from human brains which were stored frozen in the 1930s, at least two decades before the benzodiazepines were developed. While there is no evidence that the benzodiazepine structure can be synthesized enzymatically in the mammalian brain, several other compounds of this type have since been isolated from cattle brain and from human breast milk. One possibility is that gastrointestinal flora can partially synthesize the benzodiazepine molecule and it is also known that plants such as wheat and potatoes are a potential source of diazepam, desmethyldiazepam and lormetazepam. If it is eventually shown that the local brain concentration of these benzodiazepines is sufficiently high to activate the benzodiazepine receptors then the possibility arises that anxiety disorders could result from a lack of these endozepines. 

Izquierdo Medina NATURALLY OCCURRING BENZODIAZEPINES Structure, Distribution and Function... 

Cyclopyrrolones. The cyclopyrrolones were among the earliest non-benzodiazepine structures shown to have high affinity for the BZR The best-known member of this series is zopiclone (61), which is available as a... 

In the last few years new anxiolytic agents have emerged which act by a variety of mechanisms, including GABAa receptor modulation [60], More recently, anxiolytics with non-benzodiazepine structures have been reported which are described below. 

Compound 24 is a gamma-aminobutyric acid (GABA) receptor modulator that interacts with the GABA-A sub-type which is, in turn, the same locale where the classical benzodiazepine anxiolytics are also thought to interact (diazepam or Valium being a common benzodiazepine structure shown above as 57). Although 24 is classed as a nonbenzodiazepine sedative-hypnotic because it has... 

CNS drugs Benzodiazepines Structure-based Drug design... 

The original reaction discovered by Pechmann involved the cycloaddition of diazomethane and acetylene. Although a better understanding of the reaction has led to the common use of more electron-deficient alkynes, diazomethane continues to be synthetically useful. A recent elegant example of the use of diazomethane as the 1,3-dipole was demonstrated in the preparation of 2,3-benzodiazepine derivatives as potential non-competitive AMPA antagonists. " Beginning with the alkyne, the pyrazole moiety could be incorporated into the benzodiazepine structure, using the Pechmann pyrazole synthesis, to produce the 2,3-benzodiazepines. 

The benzodiazepine moiety has proven its high pharmacological activity in many respects as the examples in Fig. 37 show [12]. Therefore it seemed attractive to incorporate the benzodiazepine structure also in a peptide chain so that the heterocycle has a defined orientation with respect to the peptide backbone and may interact with a suitable receptor protein. In principle the distance of the benzodiazepine from the peptide strand may be regulated by the number of the carbon atoms between the nitrogen atoms in the peptide bond and the endocyclic N-4. We chose the 1,3-distance and took BAZ (Z enzodmzepino alanine 101) as... 

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