Current Topics in Medicinal Chemistry - Volume 8, Issue 12, 2008

Decades ago, in the 1950s, dopamine (DA) and serotonin (5-hydroxytriptamine, 5-HT) were discovered in the mammalian central and peripheral nervous systems and successively their role as essential neurotransmitters was revealed. Advances in understanding the effect of DA and 5-HT have represented one of the success stories of neuropharmacology. In these years an enormous amount of experimental evidence has revealed the pivotal role of these biogenic amines in a bewildering diversity of behavioural and physiological processes. This is not surprising, considering the large distribution of DA- and 5-HT-containing axon terminals throughout the central nervous systems (CNS), although these monoamines are synthesized by a small group of neurons within the brain stem. There are 3 major DA systems in the brain. The nigrostriatal pathway originates from cell bodies which reside in the substantia nigra pars compacta (SNc) and project to the dorsal striatum (caudate-putamen). Degeneration of these neurones results in the motor deficits of Parkinson's disease (PD). The mesolimbic pathway originates in the ventral tegmental area (VTA) and project primarily to the ventral striatum/nucleus accumbens (NAc). The mesocortical pathway also originates in the VTA but projects to the prefrontal cortex where it is thought to regulate cognitive processes such as attention and working memory. Regarding the serotonergic system, this is one of the most diffusively organized projection systems of the mammalian brain. The majority of the neurons containing 5-HT generically called the raphe nuclei are located in the brainstem and in some regions of the reticular formation. Serotonergic neurones innervate virtually all regions of the CNS including both the SNc and the VTA and their terminal areas. Thus, at neuroanatomical levels there is a close relationship between 5-HT and DAcontaining neurones and this suggests that 5-HT could regulate the function of DA neurons via actions on midbrain DA cell bodies and on DA terminals. Recent receptor discoveries have permitted the identification and classification of up to seven families of 5-HT receptors (5- HT1-5-HT7) and five DA receptor sub-types have been classified to date (D1 through D5). All 5-HT receptors belong to the seven transmembrane domain G-protein-coupled receptor (GPCR) superfamily, except for the 5-HT3 receptor which is a ligand gated channel. The 5-HT1 receptor class is comprised of five receptor subtypes (5-HT1A, 5- HT1B, 5-HT1D, 5-HT1E and 5-HT1F), which, in humans, share 40-63% overall sequence identity and couple preferentially, although not exclusively, to Gi/o to inhibit cAMP formation. Among the multiple classes of 5-HT receptors described in the CNS, much attention has been devoted to the 5-HT2 receptor family since it has been shown by experimental and clinical observation to represent a possible therapeutic target for the development of drugs for a range of CNS disorders such as schizophrenia, depression, drug abuse, eating disorders, PD and epilepsy. Indeed, 5-HT2 receptors are major targets for a wide array of psychoactive drugs, ranging from non-classical antipsychotic drugs, anxiolytics and anti-depressants, which have a 5- HT2 antagonistic action, to hallucinogens, which are agonists of the 5-HT2 receptors. Furthermore, recently it has been shown that 5-HT2 receptors have a potential significance in brain development, and in experience-dependent plasticity in the visual cortex..........

Since the initial observations linking 5-HT to psychiatric illness, evidence for a role of 5-HT and, in particular, a decreased brain serotonergic function in the pathology of a plethora of related disorders, has grown. However, it is the role of 5-HT in the pathogenesis of anxiety disorders and depression and the mechanism of action of antidepressants which has received the most attention. Thus enhanced serotonergic neurotransmission has become one of the unifying mechanisms of action of modern day antidepressants / anxiolytics such as monoamine oxidase inhibitors, tricyclic antidepressants, and serotonin reuptake inhibitors. Interestingly all of these treatments are associated with a delay to therapeutic efficacy and in some cases treatment resistance, despite immediate enhancements in serotonergic neurotransmission. The postulated reason for this is the need for temporal neuroplastic changes in the control of serotonergic neurotransmission, and more specifically changes in 5-HT1 autoreceptor function. Thus significant research has gone into pharmacologically targeting these 5-HT1 autoreceptors as a means of augmenting the efficacy of current therapeutic mechanisms. Here we will review the rationale behind the various augmentation strategies adopted and the progress made in identifying novel therapeutics for conditions such as depression and anxiety disorders.

The serotonin receptor subtype 5-HT1A was one of the first serotonin receptor subtypes pharmacologically characterized. Over the last twenty years the 5-HT1A receptor has been the object of intense research efforts as witnessed by the 5-HT1A acting drugs marketed as anxiolytics. In recent years, several new chemical entities targeting the 5-HT1A receptor (alone or in combination with other molecular targets) have been proposed for novel therapeutic indications (neuroprotection, cognitive impairment, Parkinson Disease and related disorders, pain treatment). The present review will focus on those 5-HT1A receptor agents that entered preclinical trials starting from 2000.

Recently, the serotonin 5-HT6 receptor has been identified as a drug target for attenuating cognitive deficits associated with Alzheimer's disease (AD). Additionally, this receptor may also play a role in schizophrenia, anxiety and obesity. Reports in the literature suggest that the production of selective antagonists for the 5-HT6 receptor has increased during the last 10 years, with some compounds currently in clinical trials for the treatment of AD. In this review, we will address the rationale for using 5-HT6 receptor antagonists in AD, as well as report on current advances in the understanding of the structure-activity relationships required to synthesize 5-HT6 receptor antagonists.

This review describes symptoms and pathophysiology of Parkinson's diseases (PD) and restless legs syndrome (RLS), and discusses the relationship between clinical outcome of DA agonists and their receptor-binding and pharmacokinetics. Oral DA agonists are divided into 2 classes; the ergots and the non-ergots. Both classes are in general equally effective against PD motor symptoms. Ergots (apart from bromocriptine) stimulate the DA D1 subreceptor and increase dyskinesia. Furthermore, valvular heart disease (VHD) and pulmonary and retroperitoneal fibrosis appear to represent a class effect of 8β-aminoergolines as cabergoline and pergolide The side effects profile therefore seems more beneficial for non-ergots than ergots. The main improvement of motor functions by DA agonists is related to D2 agonism. However, in monotheraphy, the selective D2-receptor DA agonist sumanirole seemed less effective than ropinirole which is selective for D2- like DA-receptors (D2, D3 and D4). Given as adjunctive to L-dopa both drugs had equal efficacy on motor-symptoms, indicating that D2-receptor activity must be accompanied with stimulation of other DA receptors for optimizing the efficacy on motor symptoms. Striatal D3 receptor loss may be more important than D2 receptor loss for reduced response to dopaminergic treatment. D3 stimulation may also be beneficial for the non-motor symptom depression/mood in PD and for neuron-protection. This makes D3-receptors a potential therapeutic target in PD. 5-HT1Areceptor agonism and α2 adrenergic antagonism may contribute to prevention of dyskinesia. However, 5-HT-receptor activity is also associated with side effects. 5-HT2B agonism (and possibly 5-HT1B agonism) is associated with fibrotic reactions, and valvular heart disease (VHD). By interfering with the CYP450 system DA agonists may contribute to drugdrug interactions. Lack of CYP2D6 activity is also suggested as important for etiology and CNS-symptoms of PD. Based on current knowledge D2-like receptor activities (preferences for the D3 receptor) seem most beneficial. 5-HT1A-receptor agonism (prevention of dyskinesia), 5-HT2B antagonism or no 5-HT2B-receptor activity also seems beneficial. Development of DA agonists containing these properties, without interfering with CYP2D6 may be beneficial.

A remarkable diversity of psychiatric and neurological disorders have been associated with dysfunction of dopamine (DA)-containing neurons, including schizophrenia, bipolar disorder (BD), Parkinson's disease (PD), and restless legs syndrome (RLS). In such disorders, transmission in discrete DA pathways may range from hypoactivation to hyperactivation of DA receptors, particularly those of the D2 subtype, providing the rationale for treatment approaches that activate or block D2 receptors, respectively. However, full agonists or pure D2 receptor antagonists may not be optimal therapeutic approaches for their respective disorders for a number of reasons, including an inability to restore the aberrant DA pathways to a normal level of basal tone. D2 receptor partial agonists (D2PAs) are proposed to stabilize activity in DA pathways by dampening excessive (and/or by restoring deficient) D2 receptor stimulation thereby shepherding DA neurons back to a desired level of basal activity. Stabilizing aberrant DA activity without disrupting nondysfunctional DA neurons may provide a potentially improved approach for treating DA disorders. The status of DA D2PAs and their potential application to schizophrenia, BD, PD, and RLS is reviewed. Preclinical and clinical evidence supports the idea that dysfunctions of D2 receptors contribute to these CNS disorders. Diseases in which both hyper- and hypofunction of DA pathways are present may be particularly promising, and challenging, targets for D2PAs. Furthermore, different DA disorders may respond optimally to D2PAs with differing levels of intrinsic activity, with “DA deficiency” diseases responding more effectively to higher intrinsic activity D2PAs than “DA hyperactivation” diseases. Overall, current evidence supports the conclusion that D2PAs have significant potential as improved CNS therapies relative to classic full agonists and antagonists at D2 receptors.

Dopamine agonists have been usually used as adjunctive therapy for the cure of Parkinson's disease. It is generally believed that treatment with these drugs is symptomatic rather than curative and it does not stop or delay the progression of neuronal degeneration. However, several dopamine agonists of the D2-receptor family have recently been shown to possess neuroprotective properties in different in vitro and in vivo experimental Parkinson's disease models. Here we summarize some recent molecular evidences underlining the wide pharmacological spectrum of dopamine agonists currently used for treating Parkinson's disease patients. In particular, the mechanism of action of different dopamine agonists does not always appear to be restricted to the stimulation of selective dopamine receptor subtypes since at least some of these drugs are endowed with antioxidant, antiapoptotic or neurotrophic properties. These neuroprotective activities are molecule-specific and may contribute to the clinical efficacy of these drugs for the treatment of chronic and progressive neurodegenerative diseases in which oxidative injury and/or protein misfolding and aggregation exert a primary role.

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