Current Medicinal Chemistry -Central
Nervous System Agents, Volume 4, No. 3, 2004
Contents
Guest Editor: Maria L. Lopez-Rodriguez
The
Anandamide Degradation System as Potential Target for the Treatment of Central
Nervous System Related Disorders Pp.155-160
Metabolism
of the Endocannabinoids Anandamide and 2-Arachidonoyl Glycerol, A Review, with
Emphasis on the Pharmacology of Fatty Acid Amide Hydrolase, A Possible Target
for the Treatment of Neurodegenerative Diseases and Pain Pp.161-174
Christopher J.
Fowler
Involvement
of the Endocannabinoid System in Motor Disorders Pp.175-182
J.J. Fernandez-Ruiz,
I. Lastres-Becker, A. Cabranes, E. de Lago and J.A. Ramos
Involvement
of the Endogenous Opioid System in Cannabinoid Responses Pp.183-193
Olga Valverde,
Patricia Robledo and Rafael Maldonado
The
Potential Role of the Endocannabinoid System in the Control of Multiple
Scleorsis Pp.195-202
David Baker and
Gareth Pryce
Serotonin
5-HT7 Receptor Antagonists Pp.203-214
M.L.
Lopez-Rodriguez, B. Benhamu, M.J. Morcillo, E. Porras, J.L. Lavandera and L.
Pardo
Abstracts
[Back to top] The
Anandamide Degradation System as Potential Target for the Treatment of Central
Nervous System Related Disorders
Maria L. Lopez-Rodriguez and Silvia
Ortega-Gutierrez
The inactivation of anandamide, the main and most widely studied endocannabinoid to date, has progressively gained support as a process of crucial importance in controlling the biological action both in time and place of this N-acylethanolamine. Within the components that account for the inactivation of anandamide, the membrane anandamide transporter (ANT) constitutes a focus of major attention since it represents one of the most important therapeutic possibilities to enhance the endocannabinoid signalling pathways avoiding the undesirable psychotropic side effects elicit by the action of other direct exogenous agonists in the central nervous system (CNS). The potential implications of the ANT in several CNS-related pathologies, together with the current hypotheses under investigation about its therapeutic applications as well as the most recent additions to the family of compounds able to inhibit the anandamide uptake, are discussed in this review.
[Back to top] Metabolism of the
Endocannabinoids Anandamide and 2-Arachidonoyl Glycerol, A Review, with
Emphasis on the Pharmacology of Fatty Acid Amide Hydrolase, A Possible Target
for the Treatment of Neurodegenerative Diseases and Pain
Christopher J. Fowler
There is a good evidence to suggest that activation of cannabinoid receptors may be beneficial not only in the treatment of conditions such as pain, but even in neurodegenerative states, such as in stroke and trauma. Nevertheless, the major obstacle to the development of cannabinoid receptor agonists as therapeutic agents for the treatment of such disorders the psychomotor are effects resulting from cannabinoid receptor activation. An alternative approach, which may avoid these problems is to bolster up tonically active endocannabinoid signalling by preventing the metabolism of the signalling molecules. In the present article, the metabolism of the endocannabinoids anandamide and 2-arachidonoylglycerol are reviewed, with the main emphasis being placed upon the pharmacology of fatty acid amide hydrolase (FAAH). This enzyme catalyses the hydrolysis of anandamide, as well as of the related N-acyl ethanolamines palmitoylethanolamide, stearoylethanolamide and oleoylethanolamide, which modulate the effects of anandamide as well as having cannabinoid receptor-independent actions of their own. A number of FAAH inhibitors have been synthesized and characterised pharmacologically. A case is made that such compounds may be useful for the treatment of pain and some neurodegenerative states. Although no FAAH inhibitors are as yet in clinical use, there is some evidence to suggest that FAAH inhibition contributes to the antinociceptive actions of spinally administered non-steroidal anti-inflammatory agents.
[Back to top] Involvement
of the Endocannabinoid System in Motor Disorders
J.J. Fernandez-Ruiz,
I. Lastres-Becker, A. Cabranes, E. de Lago and J.A. Ramos
New data strengthen the idea of a prominent role for the endocannabinoid signalling system in the modulation of a wide variety of neurobiological functions. Among these, one of the most important is the control of movement. Cannabinoid CB1 receptors are abundantly concentrated in the basal ganglia and their activation by plant-derived or synthetic cannabinoids, as well as by their endogenous ligands, modulates the activity of various neurotransmitters thus producing an hypokinetic action. This fact, together with the occurrence of marked alterations in CB1 receptors in the basal ganglia of patients affected by several motor disorders, an event that has been corroborated in animal models, has encouraged the research on the therapeutic potential of cannabinoid-based compounds to alleviate symptoms in these disorders. In addition, cannabinoids are also neuroprotective and might provide additional benefits by delaying/arresting the progress of neurodegeneration in Parkinson´s disease, Huntington´s chorea and other motor neurodegenerative disorders. This article will review the involvement of the endocannabinoid system in the basal ganglia functionality, trying to establish the future lines for the research on the therapeutic potential of cannabinoid-based compounds in motor disorders.
[Back to top] Involvement of
the Endogenous Opioid System in Cannabinoid Responses
Olga Valverde, Patricia Robledo and Rafael
Maldonado
The opioid and cannabinoid systems share a multiplicity of effects at biochemical and behavioural levels. Both opioid and cannabinoid agonists inhibit adenylyl cyclase activity, and increase the activity of MAP kinase pathways. They also produce similar changes in the permeability of several ion channels, and inhibit neurotransmitter release. Anatomical studies show that CB1 cannabinoid receptors and mu opioid receptors have a similar distribution in the central nervous system and are localised in the same neurons. Behavioural effects induced by opioids and cannabinoids include hypolocomotion, hypothermia, antinociception, and reward. Reciprocal interactions between the cannabinoid and opioid systems have been demonstrated for several responses including nociception, the development of tolerance and dependence, and the rewarding properties. In this review, the literature concerning the participation of the opioid system in the acute and chronic effects induced by cannabinoids will be discussed.
[Back to top] The Potential Role of the Endocannabinoid
System in the Control of Multiple Scleorsis
David Baker and Gareth Pryce
Multiple sclerosis (MS) is a neurodegenerative disease caused by repeated inflammatory/demyelinating events within the central nervous system (CNS). In addition to relapsing-remitting neurological insults, patients are often left with residual, troublesome symptoms such as spasticity and pain. These greatly diminish “quality of life” and have prompted some patients to self-medicate and perceive benefit from cannabis. Recent advances in cannabinoid biology are now beginning to underpin these anecdotal observations, notably that spasticity is tonically regulated by the endogenous cannabinoid system. Recent clinical trials may indeed suggest that cannabis has some potential to relieve, pain, spasms and spasticity in MS. However, because the CB1 cannabinoid receptor mediates both the positive and adverse effects of cannabis, therapy will invariably be associated with some unwanted, psychoactive effects because cannabis will target CB1 both in motor and cognitive centres. However, in an experimental model of MS, at least, there are local perturbations of the endocannabinoid system in lesional areas. Stimulation of endocannabinoid activity in these areas either through increase of synthesis or inhibition of endocannabinoid degradation offers the therapeutic potential of the cannabinoid system whilst limiting adverse events by locally targeting the lesion. In addition, this may also have neuroprotective potential as the endocannabinoid system controls the level of neurodegeneration that occurs as a result of the inflammatory insults. Therefore, cannabinoids may not only offer symptom control but may also slow the neurodegenerative disease progression that ultimately leads to the accumulation of disability.
[Back to top] Serotonin 5-HT7
Receptor Antagonists
M.L. Lopez-Rodriguez, B. Benhamu, M.J. Morcillo, E. Porras, J.L. Lavandera and L. Pardo
The 5-HT7R is the most recent addition to the burgeoning family of serotonin receptors. Preliminary evidences suggest that it may be involved in depression, control of circadian rhythms, and relaxation in a variety of vascular smooth muscles, indicating the high potential of 5-HT7R ligands as new therapeutic drugs. During the last four years several selective 5-HT7R antagonists have been discovered, and we have recently contributed to this field with the definition of a pharmacophoric hypothesis for 5-HT7R antagonism and a computational model of ligand-receptor interaction of new naphtholactam and naphthosultam derivatives acting at this receptor. This article will review the development of 5-HT7R antagonists with an emphasis on selective antagonists, their structural requirements and ligand-receptor interactions, as well as the potential therapeutic opportunities surrounding 5-HT7R ligands.