HT receptor subtypes

Panic Miracle System

The Panic Miracle

Get Instant Access

Current knowledge of 5-HT receptors has been derived from advances in medicinal chemistry, from the synthesis of ligands that show considerable specificity for subpopulations of 5-HT receptors. The application of such ligands to our understanding of the distribution of the 5-HT receptor subtypes has been largely due to quantitative in vitro autoradiographic techniques and the application of such imaging techniques as positron emission tomography. Functional studies undoubtedly lag behind but the development of sophisticated electrophysiological techniques and studies of changes in secondary messenger systems which respond to the binding of selective ligands to the 5-HT receptor subtypes have opened up the probability that the physiological importance of the numerous receptor subtypes will soon be clarified.

Figure 6.1. Main serotonergic pathways in the human brain. The higher centres of the brain are innervated by the serotonergic tracts originating from the rostral raphe nuclei while the cerebellum and spinal cord are innervated from tracts originating from the caudal raphe.

Figure 6.1. Main serotonergic pathways in the human brain. The higher centres of the brain are innervated by the serotonergic tracts originating from the rostral raphe nuclei while the cerebellum and spinal cord are innervated from tracts originating from the caudal raphe.

As a consequence of the application of these various techniques, the International Union of Pharmacological Societies (IUPHAR) Commission on serotonin nomenclature has published two major reports which attempt to classify the various receptor subtypes according to their ligand binding properties and secondary messenger systems. The first report classified 5-HT receptors into 5-HTj-like (comprising 5-HT1A, 1B, jc and 1D), 5-HT2 (formerly the 5-HT-D receptor) and 5-HT2 (formerly the 5-HT-M receptor). The detection of a novel 5-HT receptor, that could not be classified as 5-HT1, 5-HT2 or 5-HT3, in both the peripheral and central nervous systems, extended the receptor types to 5-HT4. The application of molecular biology techniques has led to the cloning and sequencing of at least six different 5-HT receptors, namely 5-HT1A, 5-HT1B, 5-HT1c, 5-HT1D, 5-HT2 and 5-HT3. Further studies of the second messenger systems to which these receptor subtypes are attached have shown that the 5-HT1-like, 5-HT2 and 5-HT4

receptors belong to the G protein coupled receptor superfamily, whereas the 5-HT3 receptor belongs to the same family as the nicotinic, gamma-aminobutyric acid-A (GABA-A) and glycine receptors which are ion gated channel receptors.

The most recent publication of the IUPHAR Commission has redefined the 5-HT receptor subtypes according to their second messenger associations and thereby helped to stress the functional role of the receptor subtypes rather than relying primarily on the specificities of ligands that bind to them. This approach has led to the classification of 5-HT receptors into those linked to adenylate cyclase (5-HT1A, 5-HT1B, 5-HT1D, 5-HT4), those linked to the phosphatidyl inositol system (5-HT2A, 5-HT2B and 5-HT2c), and those linked directly to ion channels (5-HT3). Table 6.1 summarizes the accepted classification of the 5-HT receptor subtypes, all of which occur in the brain, together with the most specific agonists and antagonists which have been developed. The structures of the seven subtypes of the serotonin receptor have now been determined. Apart from the ionotropic 5-HT3 receptors (Figure 6.2), the other receptors are of the metabotropic type (Figure 6.3, 5-HT2 receptor). Figure 6.4 illustrates the molecular structure of the 5-HT4 receptor.

More recently, the family of 5-HT receptors has been dramatically increased to include 5-HT4, 5-HT5A and 5-HT5B, 5-HT6 and 5-HT7. The 5-HT6 and 5-HT7 receptors are positively linked to adenylate cyclase. Of these, only the 5-HT4 receptor has so far not been cloned. Of these newly discovered receptors, only the 5-HT4 receptor has been investigated in some detail. This receptor is quite widely distributed in the brain and peripheral tissues where they are positively coupled to adenylate cyclase. In the brain, the 5-HT4 receptors facilitate acetylcholine release and may play a role in peristalsis. It has been hypothesized that in the brain 5-HT4 receptors may also play a role in facilitating cholinergic transmission and thereby have a potential role to play in preventing cognitive deficits which are associated with cortical cholinergic malfunction. The possible clinical significance of 5-HT4 receptors must await the development of specific agonists and antagonists. So far, such compounds have not been developed. Figures 6.5, 6.6 and 6.7 illustrate the distribution of 5-HT3, 5-HT4, 5-HT6 and 5-HT7 receptors in the human brain.

Despite the dramatic advances which have taken place in the identification and characterization of 5-HT receptor subtypes, it is evident that many of the ligands used to characterize these receptor subtypes are not completely selective. It must also be emphasized that receptors are the products of genes and are therefore subject to genetic changes and, as a consequence, variability in physiological and pharmacological responsiveness. Thus affinity, potency and intrinsic activity of a drug at one receptor may vary depending on the time, species and receptor-effector coupling. It

Table 6.1. Distribution and selectivity of drugs for 5-HT receptor subtypes

5-HT1A receptors

Hippocampus, septum, amygdala, cortical limbic area Agonists: buspirone, gepirone, ipsapirone, flesinoxan Antagonists: WAY 100135, BMY7378, NAN-190 Possible clinical use of agonists: anxiolytics, antidepressants 5-HT1B receptors

Substantia nigra, globus pallidus, dorsal subiculum, superior colliculi Non-selective: pinodol, propanolol ? selective partial agonists: CP-93, 129 Possible clinical use of antagonists: antidepressants 5-HT1D receptors

Caudate nucleus but widely distributed in human dry and GP brain, similar to 5-HT1B of rat brain Non-selective: rauwolscine, yohimbine ? selective: L-694, 247

Possible clinical use of antagonists: antidepressants 5-HT1E receptor

In mammalian brain Possible clinical use: ? 5-HT2A

Neocortex but widely distributed in the mammalian brain Agonists: DOI, DOB

Non-selective antagonists: ketanserin, ritanserin

Possible clinical use of antagonists: antidepressants, anxiolytics, ? neuroleptics 5-HT2B In mammalian brain Possible clinical use: ? 5-HT2C Choroid plexus

Non-selective antagonists: spiperone, amperozide, pimozide Possible clinical use of antagonists: neuroleptics 5-HT3

Area postrema, entorhinal and frontal cortex, hippocampus Agonists: ondansetron, granisetron, zacopride

Possible clinical use of antagonists: antiemetics, anxiolytics, ? antidementia 5-HT4

Collicular and hippocampal neurons Antagonists SC-205-557, SC-53606 Agonist: SC-49518 Possible clinical use: ?

8-OHDPAT=Dipropylamino-8-hydroxy-1/2/3/4-tetrahydronaphthylene

RU-24969 = 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl) 1H indol mCPP = 1-(3 chlorophenyl) piperazine

TFMPP = 1-(m-trifluoromethylphenyl) piperazine

DOI = 1-(2,5-dimethoxy-1-iodophenyl) 2-aminopropane

MDL 73005 = 8,2 (2,3-dihydro-1,4-benzodioxin-2yl) methylamino-ethyl-8-azaspirol (4,5) decan-7,9-dione NAN 190 = 1-(2-methoxyphenyl) 4-(4(2-phthalimido)entyl-piperazine) 5-CT = 5-carboxamidotryptamine

ICI169369 = (2-(2-dimethylamino-ethylthio-3-phenylquinoline)) ICS 205-930 = (3-tropanyl)-IH-indole-2-carboxylic acid ester DOM = 2,5-dimethoxy-4-dimethylbenzene ethamine

5-H-Rreceptor synaptic cleft

5-H-Rreceptor synaptic cleft

Figure 6.2. Diagrammatic representation of the 5-HT3 receptor. The 5-HT3 receptor is distinct from the other 5-HT receptor subtypes, in that it is a ligand gated ion channel that is permeable to sodium and potassium. The 5-HT3 receptor is structurally similar to the nicotinic acetylcholine receptor and is composed of five sub-units. Two sub-units have been cloned, 5-HT3A and 5-HT3B, and homomeric (5-HT3A) and heteromeric (5-HT3A/5-HT3B) forms of the receptor have both been characterized.

Figure 6.2. Diagrammatic representation of the 5-HT3 receptor. The 5-HT3 receptor is distinct from the other 5-HT receptor subtypes, in that it is a ligand gated ion channel that is permeable to sodium and potassium. The 5-HT3 receptor is structurally similar to the nicotinic acetylcholine receptor and is composed of five sub-units. Two sub-units have been cloned, 5-HT3A and 5-HT3B, and homomeric (5-HT3A) and heteromeric (5-HT3A/5-HT3B) forms of the receptor have both been characterized.

is already known, for example, that ipsapirone, buspirone, spiroxatrine and lysergic acid diethylamide (LSD) may behave either as agonists or antagonists depending on the functional model being used to assess their activity. A similar problem arises with intrinsic activity which is usually assumed to be a direct reflection of the pharmacological properties of the drug. It seems possible that the affinity can also be influenced by the nature of the genetically determined receptor-effector coupling and is therefore tissue (and species) dependent. Such factors may help to explain why the identification and subclassification of 5-HT receptor subtypes is complex and often confusing.

This dilemma can be illustrated by the attempts being made to identify the functional role of 5-HT receptor subtypes using ligands which are believed to be specific in their binding properties. Such ligands may prove to be non-selective, more selective for an as yet unidentified 5-HT receptor subtype or more selective for a non-5-HT receptor site. Conversely several non-5-HT ligands are known to bind to 5-HT receptors with a high affinity. For example, the alpha1 adrenoceptor antagonist WB4101, and the beta adrenoceptor antagonist pindolol, have a high affinity to 5-HT1A receptors.

Figure 6.3. Diagrammatic representation of the 5-HT2 receptor. The 5-HT2 receptor consists of three subtypes (5-HT2a,2B and 2c). All are metabotropic in their action but have different physiological properties (see text for details).

S-HT receptor amino (N) terminal

Was this article helpful?

0 0
Anxiety Away

Anxiety Away

The strategies revealed within Anxiety Away are fast acting, simple and guaranteed to work even if you have suffered from anxiety for a long time!

Get My Free Ebook


Post a comment