Current Medicinal Chemistry -Central Nervous System Agents, Volume 3, No. 1, 2003

Current Medicinal Chemistry - Central Nervous System Agents, Volume 3, No. 1, 2003

Contents

Glutamate mGluR₅-Adenosine A_2A-Dopamine D₂ Receptor Interactions in the Striatum. Implications for Drug Therapy in Neuro-psychiatric Disorders and Drug Abuse Pp. 1-26

Sergi Ferre, Francisco Ciruela, Amina S. Woods, Meritxell Canals, Javier Burgueno, Daniel Marcellino, Marzena Karcz-Kubicha, Bruce T. Hope, Marisela Morales, Patrizia Popoli,Steven R. Goldberg, Kjell Fuxe, Carme Lluis, Rafael Franco and Luigi Agnati

[Abstract]

Serotonin Type-4 (5-HT₄) Receptors as Therapeutic Targets: Past and Future Roles of 5-HT₄ Receptor Agonists Pp. 27-36

Henri Mattes, and Hans-Juergen Pfannkuche

[Abstract]

Serotonin Type-4 (5-HT₄) Receptors as Therapeutic Targets: 5-HT₄ Receptor Antagonists Pp. 37-42

Henri Mattes, and Hans-Juergen Pfannkuche

[Abstract]

New Approaches in the Treatment of Overactive Bladder: Targeting Adrenergic Receptors and Neurokinin Receptors Pp. 43-47

O. Ishizuka

[Abstract]

The Therapeutic Potential of Amphetamines in Post-stroke Recovery Pp. 49-55

Anwar Khokar, Jawad F. Kirmani, Andrew R. Xavier and Adnan I. Qureshi

[Abstract]

Membrane Pathology in Schizophrenia: Implication for Arachidonic Acid Signaling Pp. 57-65

Jeffrey K. Yao, and Ravinder D. Reddy

[Abstract]

Abstracts

[Back to top] Glutamate mGluR₅-Adenosine A_2A-Dopamine D₂ Receptor Interactions in the Striatum. Implications for Drug Therapy in Neuro-psychiatric Disorders and Drug Abuse

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 A_2A-dopamine D₂ and adenosine A_2A-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 A_2A-D₂ and A_2A-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-A_2A-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-A_2A-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.

[Back to top] Serotonin Type-4 (5-HT₄) Receptors as Therapeutic Targets: Past and Future Roles of 5-HT₄ Receptor Agonists

Henri Mattes, and Hans-Juergen Pfannkuche

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 treatment of functional motility disorder s of the gastrointestinal tract. A survey of 5-HT ₄ receptors, their distribution and function, will be provided. 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.

[Back to top] Serotonin Type-4 (5-HT₄) Receptors as Therapeutic Targets: 5-HT₄ Receptor Antagonists

Henri Mattes, and Hans-Juergen Pfannkuche

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.

[Back to top] New Approaches in the Treatment of Overactive Bladder: Targeting Adrenergic Receptors and Neurokinin Receptors

O. Ishizuka

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, a1A, a1B, a1D, a2A, a2B, a2D, b1, b2, b3. Recently, a1D 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.

[Back to top] The Therapeutic Potential of Amphetamines in Post-stroke Recovery

Anwar Khokar, Jawad F. Kirmani, Andrew R. Xavier and Adnan I. Qureshi

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.

[Back to top] Membrane Pathology in Schizophrenia: Implication for Arachidonic Acid Signaling

Jeffrey K. Yao, and Ravinder D. Reddy

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.