Carbamazepine structure

Epilepsy is a clinical disorder characterized by spontaneous, recurrent seizures arising from excessive electrical activity in certain parts of the brain [51]. Currently available drugs, such as phenytoin, carbamazepine, valproic acid, lamotrigine, and topiramate (for molecular structures see Fig. 6), provide symptomatic seizure suppression in only 60-70% of those receiving treatment [52-54]. These drugs are also associated with unwanted side... 

Oxcarbazepine (a prodrag) is structurally related to carbamazepine, but it is converted to a monohydrate derivative, which is the active component. 

Although simple intensity correction techniques can be used to develop very adequate XRPD methods of quantitative analysis, the introduction of more sophisticated data acquisition and handling techniques can greatly improve the quality of the developed method. For instance, improvement of the powder pattern quality through the use of the Rietveld method has been used to evaluate mixtures of two anhydrous polymorphs of carbamazepine and the dihydrate solvatomorph [43]. The method of whole pattern analysis developed by Rietveld [44] has found widespread use in crystal structure refinement and in the quantitative analysis of complex mixtures. Using this approach, the detection of analyte species was possible even when their concentration was less than 1% in the sample matrix. It was reported that good quantitation of analytes could be obtained in complex mixtures even without the requirement of calibration curves. 

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],... 

The major metabolic pathway of carbamazepine is an example of this oxidation as shown in Figure 4.73. The usual bond angle of a sp3-hybridized carbon is 109°, but it is constrained to be 60° in an epoxide making epoxides reactive. This reactivity varies significantly depending on the structure of the epoxide, and this will be discussed further in Chapter 8. The epoxide of carbamazepine is relatively unreactive and easy to isolate. 

Hilfiker et al. at Solvias used carbamazepine (CBZ) as a model compound to describe the use of Raman microscopy to characterize crystal forms, including during solvent evaporation experiments [228], The spectra were processed into clusters by spectral similarity. The authors note that all published and several new crystal forms were identified during the study. Solvias HTS uses a specific set of crystallization protocols that have tended to produce new polymorphs. Hilfiker notes that Raman microspectroscopy is an ideal analytical tool for high-throughput discrimination between crystal structures. [229], The ability to collect spectra directly and automatically in a microtiter plate with or without solvent and during evaporation is a major advantage over many other techniques. 

Carbamazepine is a tricyclic iminostilbene derivative and structurally related to the tricyclic antidepressants. It is used as a first-line agent for the management of generalized tonic-clonic epilepsy. It is also highly effective for partial seizures but has no efficacy in patients with absence seizures or atonic seizures. In epilepsy it supposedly has the same mechanism of action as phenytoin. An other well... 

Rosen JB, Weiss SRB, Post RM Contingent tolerance to carbamazepine alterations in TRH mRNA and TRH receptor binding in limbic structures. Brain Res 651 252-260, 1994... 

Structural and theoretical chemistry studies of phenytoin and carbamazepine suggest that they bind to the Na+ channel via a pharmacophore that consists of an aromatic ring and an amide linkage. This pharmacophore consists of two of the three structural features found in local anesthetics. The ionizable group, which is characteristic of local anesthetics, precludes the ability to diffuse across the blood-brain barrier. 

Post and Kramlinger (386) have also suggested that lithium added to carbamazepine may be useful in treatment-resistant mood-disordered patients. One possible basis for this approach is that carbamazepine, which has a tricyclic ring structure similar to imipramine, may sensitize postsynaptic serotonin receptors in a similar way to standard drugs such as imipramine. A mood stabilizer (e.g., lithium, valproate, carbamazepine) plus antidepressant may benefit some rapid cycling or mixed bipolar patients, attenuating the propensity to switch from mania to depression. 

Although not obvious from a two-dimensional representation of its structure, carbamazepine has many similarities to phenytoin. The ureide moiety (-N-CO-NH2) in the heterocyclic ring of most antiseizure drugs is also present in carbamazepine. Three-dimensional structural studies indicate that its spatial conformation is similar to that of phenytoin. 

The Division of Drug Experience of the US Department of Health and Welfare issued a note on five cases of the syndrome of inappropriate antidiuretic hormone secretion and drugs to which it has been attributed (1137). All involved drugs with a tricyclic structure one patient was taking imipramine, three carbamazepine, and the others the closely related muscle relaxant cyclobenz-aprine. The dosage of imipramine was 50 mg/day for 3 weeks and the patient was a 72-year-old woman. Other cases have been reported, involving amitriptyline (1137), imipramine, and protriptyline (SEDA-17,17). 

Two different of supramolecular synthons have been detected in the two polymorphs of the carbamazepine-saccharin cocrystal system [45]. In the Form-I structure, the carbamazepine molecules formed a homo-synthon, with the saccharine molecules also forming a hydrogen-bonded homodimer. The interaction of these two synthons resulted in formation of a one-dimensional array of molecules in a crinkled tape motif. In the Form-II structure, a heterosynthon is formed by the interaction of a carbamazepine and a saccharin molecule. This latter synthon packs in one-dimensional chains that extended along the crystallographic c-axis. 

While the polymorphic forms of carbamazepine all exhibit an anticarboxamide hydrogen-bond dimer motif, the related compounds oxcarbazepine (10-oxo-10,l l-dihydro-5H-dibenzo[fr,/]azepine-5-carboxamide) and dihy-drocarbamazepine (10,ll-dihydro-5H-dibenzo[fc/]azepine-5-carboxamide) adopt hydrogen-bond chain motifs in their crystal structures [47]. The structures of several cocrystals of the structurally related compound cyten amide (5H-dibenzo[fl,d][7]annulene-5-carboxamide) have been reported, with the details of the hydrogen-bonding patterns being discussed [48-51]. 

A.J.C. Cabeza, G.M. Day, W.D.S. Motherwell, W. Jones, Importance of molecular shape for the overall stability of hydrogen bond motifs in the crystal structures of various carbamazepine-type drug molecules, Cryst. Growth Des. 7 (2007) 100-107. 

Hydration, in the context of metabolism, is the addition of water to a structure. Epoxides are readily hydrated to diols (see carbamazepine, Table 9.1), the reaction being catalysed by the enzyme epoxide hydrolase. 

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