Current Medicinal Chemistry - Central Nervous System Agents - Volume 3, Issue 1, 2003

There is growing evidence for the existence of not only homomeric, but also functional heteromeric receptor complexes, particularly involving G protein coupled receptors (GPCRs). These include adenosine A2A-dopamine D2 and adenosine A2A-glutamate mGlu5 receptor complexes. The role of these receptor complexes in receptor function seems to be multiple, involving hetero-modulation of ligand recognition, signalling and trafficking. The preferential localization of A2A-D2 and A2A-mGlu5 receptor complexes is in the dendritic spines of striatopallidal GABAergic neurons. Results obtained from behavioral and in vivo microdialysis experiments have shown an important role of mGlu5-A2A-D2 receptor interactions in the modulation of the function of the striatopallidal GABAergic neurons. The striatopallidal GABAergic neurons play a key role in the pathophysiology of basal ganglia disorders, like Parkinson's disease, and it is a common pathway for the rewarding effects of opiates and psychostimulants and for the antipsychotic effects of neuroleptics. The formation of receptor complexes modifies the single receptor transducing characteristics and leads to the appearance of “emergent properties”. Thus, the study of mGlu5-A2A-D2 receptor interactions in the striatum reveals new properties of these GPCRs and gives indications for a new rational approach for drug therapy in neuro-psychiatric disorders and drug addiction.

Understanding the biological consequences of 5-HT4 receptor activation has been a subject of intensive research over the last decade and there is now ample evidence to suggest that activation of these receptors represents a valid approach for the trea tment of f unctional motility disorder s of the gastrointe stina l tra ct. A surve y of 5-HT 4 r ec eptor s, their distribution a nd function, will be pr ovide d. This article will also review 5-HT4 receptor agonists currently on the market, undergoing clinical development, as well as potential new agents that have been discovered.

Characterization of 5-HT 4 receptors started in the late eighties following the important finding that the potent 5-HT3 receptor antagonist, tropisetron, could act as a competitive antagonist at the newly discovered 5-HT4 receptor. During recent years several pharmaceutical companies claimed that their 5-HT4 antagonists might be useful for the treatment and / or prophylaxis of cardiovascular, CNS and gastrointestinal disorders. This paper reviews the development of 5-HT4 receptor antagonists from experimental tools towards potential therapeutic agents.

Bladder outlet obstruction, such as benign prostatic hypertrophy, and neurogenic bladder with cerebro-vascular disease and Parkinson's disease, not only cause difficulty in urination, but also overactive bladder. This overactive condition is currently a major health concern, in terms of quality of life. Bladder outlet obstruction leads to bladder hypertrophy, and changes in the nervous control of micturition. Hypertrophied detrusor muscles release nerve growth factor, which also leads to changes in nervous control of micturition, especially sympathetic nerve and c-fiber mediated control. Adrenergic receptors comprise certain subtypes, α1A, α1B, α1D, α2A, α2B, α2D, β1, β2, β3. Recently, α1D and b3 receptors are of particular interest with regard to their functional role in overactive bladder. Tachykinins are the main neuropeptides of c-fiber mediated nervous control. Normally, this c-fiber is silent, however, in pathological conditions, such as bladder outlet obstruction and neurogenic bladder, it becomes activated and causes overactive bladder. Recently, antagonists of tachykinin receptors, neurokinin (NK) 1, 2, 3, have become of interest in regard to their role in the treatment of overactive bladder.This review describes some of the changes in adrenergic and NK receptors in the central nervous system and the spinal micturition center in the overactive bladder, and a new approach to treatment that targets these receptors.

Recovery following stroke has two distinct periods: the immediate recuperative phase taking effect within the first few days, and the delayed phenomenon occurring several days later. The first phase is thought to be a secondary to resolution of brain edema and diaschisis, while the latter phase is believed to be due to neural plasticity. Neural plasticity comprises primarily neurite growth and synaptogenesis. While there have been controversial studies regarding the existence and exact nature of neural plasticity, several researchers have established behavioral recovery after stroke as a function of neuronal remodeling, that would include dendritic growth and increase in synaptic population. Nororepinephrine plays a key role in both phases of stroke recovery. Antagonist such as clonidine and alpha-1 agonists impair functional recovery when administered in the immediate post-stroke period. Sympathomimetic drugs such as amphetamines have been shown to increase functional performance that correlates with neuronal (and synaptic) growth in the brain. Most of these studies have been performed on rats, with limited work performed on human subjects. The exact dosage and timing of administration of amphetamines in the post-stroke period remains to be defined. Nonetheless, amphetamines remain a viable and exciting option for in the post-stroke “recovery” period.

Schizophrenia is a major mental disorder with no clearly identified pathophysiology. A variety of theories have been proposed to explain the pathophysiology of schizophrenia. One approach that is finding empirical support is the investigation of membrane composition and function. Evidence to date suggests that there are defects in phospholipid metabolism and cell signaling in schizophrenia. Specifically, low levels of arachidonic acid (AA)-enriched phospholipids have been observed in both central and peripheral tissues. It is well known that changes in membrane composition are associated with a variety of functional consequences. Since AA has many key roles in neural functioning, understanding its significance for the pathophysiology of schizophrenia may lead to novel approaches to improving treatment of schizophrenia. The purpose of this review is thus to explore some of the roles of AA signaling in biological, physiological, and clinical phenomena observed in schizophrenia.