Current Medicinal Chemistry - Central Nervous System Agents - Volume 2, Issue 4, 2002

Prolyl oligopeptidase is unrelated to the serine peptidases of the classical trypsin and subtilisin families. It is implicated in a variety of disorders of the central nervous system, such as amnesia and different stages of depression. It has recently been demonstrated that the enzyme is involved in the lithium sensitive signal transduction coupled with depression. Thus prolyl oligopeptidase is an important target of drug design. Some inhibitors described as cognitive enhancers have entered clinical trials. An essential property of prolyl oligopeptidase is its selectivity, which is restricted to oligopeptides comprising not more than about 30 amino acid residues. The recent crystal structure determination of prolyl oligopeptidase (80 kDa) has shown that the enzyme contains a peptidase domain with an α / β hydrolase fold, and its catalytic triad is covered by the central tunnel of an unusual seven-bladed β-propeller. This domain operates as a gating filter, excluding large, structured peptides from the active site. The binding mode of substrates and the catalytic mechanism differ in several features from that of the classical serine peptidases.

Cloned in 1991, the human dopamine D4 receptor is found mainly in cortical and limbic areas of brain. Many chemically dissimilar D4 receptor-selective antagonists have been developed, initially stimulated by partial D4 receptorselectivity of the clinically superior antipsychotic agent clozapine. Implication of D4 receptor in the pathophysiology or treatment of idiopathic psychotic disorders, however, remains elusive. Moreover, L-745,870, a selective D4 antagonist, and fananserin, a mixed antagonist of D4 and 5-HT2 receptors, failed to show antipsychotic efficacy. Interest in D4 receptor pharmacology was re-kindled by the 1996 discovery that D4 receptor gene polymorphism is associated with attention deficit-hyperactivity disorder (ADHD) and related personality traits. D4 receptors are also implicated in mood disorders and the actions of psychostimulants. Development of many chemically dissimilar D4-selective antagonists has contributed to improved understanding of D4 receptor neurobiology. This review summarizes recent advances in the synthetic chemistry of D4 receptor antagonists, and considers selected neuropharmacological studies suggestive of their potential clinical applications.

Advances in genetic engineering and expression systems have led to rapid progress in the development of antibodies fused to other proteins. These “antibody fusion proteins” combine the unique targeting ability of antibodies with the activity of the non-antibody partner. One promising application of these novel molecules is drug delivery to the brain, an organ difficult to target due to the presence of the blood-brain barrier (BBB), which effectively restricts transport from the blood of water soluble molecules larger than several hundred daltons. However, the tightly joined capillary endothelial cells, which form the BBB, have specific receptors that can be exploited by the antibody fusion proteins for transport from the blood to the brain. This can be achieved by fusing the antibody of interest to a protein with receptors on the BBB. An alternative approach is to fuse the protein of interest to an antibody specific for a BBB receptor. In both cases, antibody fusion proteins can either be the diagnostic and / or therapeutic agents themselves, or they can be used as universal vectors to deliver the desired active agent into the brain. During the last ten years multiple antibody fusion proteins have been developed for brain targeting and proof of principle has been established in animal models. The present review describes strategies for construction of antibody fusion proteins for brain targeting and discusses the in vitro and in vivo properties of these molecules.

Cholecystokinin (CCK) receptors are divided into CCK-1 (formerly CCK-A) and CCK-2 (formerly CCK-B) sub-types. CCK is a widely distributed neuropeptide in the brain and is considered a central nervous system transmitter. Possible therapeutic applications for CCK-2 antagonists include panic, anxiety, analgesia, schizophrenia, gastric disorders, and gastrointestinal tumours. This review covers the last five years findings in the field of such molecules

Although cocaine and synthetic local anesthetics block nerve conductance by blockading Na+ current, toxic doses produce seizures both in rodents and humans. It has been generally accepted that local anesthetic-induced seizures are related to their inhibition of central inhibitory nervous systems, thereby stimulating excitatory neuronal activity. Cocaine has been shown to exert psychostimulant action by inhibiting the monoamine uptake system, while synthetic local anesthetics are believed to lack this effect. However, certain local anesthetics, including procaine, display cocaine-like psychostimulating effects in animals. Recently, an inhibitory action by certain local anesthetics on monoamine transporters (MAT) has been demonstrated, and this effect relates to their psychostimulating and seizure effects. Therefore, MAT play a critical role in regulating seizures and psychostimulation. This review summarizes the inhibitory action of local anesthetics on MAT, and the influences of acute and chronic pharmacological manipulations of central nervous system functions on the central stimulating actions of local anesthetic and cocaine. The findings have important implications for safe and effective drug use and the development of new medicaments for treatment of cocaine abuse.