Amidation Blood-brain barrier

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. 

Pyrrolidine amide, (II), ENK conjugates prepared by the author (3) in a subsequent investigation were effective in traversing the blood-brain barrier and used as enkephalin delivery agents. 

Cimetidine crosses the blood-brain barrier and its adverse events include central respiratory depression and extrapyr-amidal and cerebellar disturbances. There have been convincing isolated reports of choreiform movements (3,4). 

Two conditions must be distinguished a histopathological picture characterized by diffuse perivenous focal encephalitis and a condition based on a disturbance of the blood-brain barrier, that is an encephalopathy that characteristically occurs in infants. The incubation period of postvaccinial encephalomyelitis is 9-13 days. Its onset is mostly sudden. The clinical picture varies. Mortality is high (30-50%). Recovery may be complete, but there are often neurological sequelae, such as paresis and extrapyr-amidal disturbances. 

A device for retention of a dopamine prodrug into the central nervous system has been designed by the synthesis on N-methyl-dihydronicotinoyl amides of dopamine 3,4-0-diesters, such as 23, which are converted into a quaternary pyridinium derivative by oxidation, and thereby retained inside the blood-brain barrier [19]. Only modest dopamine-like activity was observed, and this may due to a slow rate of enzymatic hydrolysis of the amide bond joining the dopamine and the pyridinium moieties. 

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