Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three chemical classes of serotonin 5-HT4 receptor agonists have been identified so far: 5-substituted indoles (e.g. 5-HT), benzamides (e.g. renzapride) and benzimidazolones (e.g. BIMU 8). In a search for 5-HT4 receptor antagonists, we have discovered that the benzimidazolone derivative DAU 6285 (for structure see text), is 3-5 times more potent than tropisetron in blocking 5-HT, renzapride and BIMU 8 induced stimulation of adenylate cyclase activity in mouse embryo colliculi neurons. Schild plot analysis yielded Ki values of 220, 181 and 255 nmol/l, respectively. In addition, DAU 6285 showed poor activity as a 5-HT3 receptor ligand with respect to tropisetron, as demonstrated by in vitro binding studies (Ki, 322 vs 2.8 nmol/l) and by its antagonistic activity in the Bezold-Jarisch reflex test (ID50, 231 vs 0.5 micrograms/kg, i.v.). No significant binding (Ki greater than 10 mumol/l) of DAU 6285 to serotonergic 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT2 receptors as well as to adrenergic alpha 1, alpha 2, dopaminergic D1, D2 or muscarinic M1-M3 receptor subtypes was found. The data indicate that DAU 6285 has a somewhat higher affinity than tropisetron for 5-HT4 receptors, a property confirmed in functional tests, and much lower affinity than tropisetron for 5-HT3 receptors. The compound represents a new interesting tool for investigating the pharmacological and physiological properties of 5-HT4 receptors.
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PMID:Characterization of a novel 5-HT4 receptor antagonist of the azabicycloalkyl benzimidazolone class: DAU 6285. 132 Feb 4

Bovine pulmonary artery smooth muscle (SM) cells express a novel 5-hydroxytryptamine (5-HT) (5-HT4-like) receptor coupled to cAMP accumulation. cAMP radioimmunoassay established the agonist and antagonist profiles of this receptor. 5-HT (EC50 = 91 +/- 33 nM) and 5-methoxytryptamine were equipotent at the SM cell 5-HT receptor and both were more potent than 5-carboxamidotryptamine. Other tryptamine derivatives were less potent but remained full agonists. These findings are consistent with previous reports regarding 5-HT4 and 5-HT4-like receptors in the central nervous system. The most potent antagonists were the antidepressant compounds nortriptyline (IC50 = 177 +/- 153 nM) and zimelidine (IC50 = 202 +/- 101 nM). The 5-HT3 and 5-HT4 antagonist 3-tropanyl-indole-3-carboxylate (ICS 205-930) was also a competitive antagonist at this 5-HT4-like receptor (pA2 = 6.3). Antagonist affinities differed slightly at the SM cell receptor, compared with other 5-HT4 and 5-HT4-like receptors in the central nervous system. Nonetheless, the SM cell 5-HT4-like receptor displayed the same differential antagonist potencies as reported for these other receptors (ICS 205-930 > MDL 72222 and mianserin > ketanserin). 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was the most potent agonist for this 5-HT4-like receptor (EC50 = 6.4 +/- 3.4 nM). 8-OH-DPAT-induced cAMP accumulation could be blocked by ICS 205-930 but not by the 5-HT1A antagonist 1-(2-methoxyphenyl)-4-[4-(2-pthalimido)butyl]piperazine hydrobromide, distinguishing the SM cell 5-HT receptor from 5-HT1A receptors. The mechanism of 5-HT-stimulated cAMP production was also investigated. First, GTP augmented basal and 5-HT-stimulated cAMP accumulation. Second, antisera to the carboxyl terminus of the alpha subunit of Gs, attenuated 5-HT-mediated adenylate cyclase activation. This established that 5-HT-stimulated cAMP accumulation in SM cells required GS. These findings suggest that SM cells express a novel 5-HT4-like receptor positively coupled to adenylate cyclase. An unexpected finding was that 8-OH-DPAT is a potent partial agonist. These studies suggest that there may be heterogeneity among 5-HT4-like receptors.
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PMID:8-hydroxy-2-(di-n-propylamino)tetralin-responsive 5-hydroxytryptamine4-like receptor expressed in bovine pulmonary artery smooth muscle cells. 133 64

In the presence of spiperone to block the 5-HT1A-mediated inhibition of pyramidal cell activity, 5-hydroxytryptamine (serotonin, 5-HT) produces a rapid transient increase in amplitude of the extracellularly recorded population spike from area CA1 of the hippocampus. Intracellular recording techniques in area CA1 of rat hippocampal slices were used to identify the ionic mechanism and to characterize the 5-HT receptor mediating this excitatory response to 5-HT. Most of the experiments were conducted in the presence of spiperone to block the 5HT1A hyperpolarization. Since spiperone also has high affinity for 5-HT2 receptors, any response mediated by 5-HT2 receptors would also be blocked. Bath perfusion of the slice with 5-HT increased the rectification of pyramidal cells in the subthreshold region, increased the resistance, and increased the amplitude of subthreshold excitatory postsynaptic potentials (EPSPs) to initiate spike firing. The 5-HT2,1C-selective agonist DOI mimicked this effect of 5-HT, and the 5-HT2,1C antagonist ketanserin (1 microM) blocked the effect of DOI. There was no change in the amplitude of the slow afterhyperpolarization (sAHP) or the amplitude of evoked inhibitory postsynaptic potentials (IPSPs). The increase in rectification and EPSP amplitude by 5-HT occurred even in the presence of the 5-HT4-selective antagonist BRL 24924 to prevent the decrease in amplitude of the sAHP by 5-HT. We conclude that 5-HT produces a fast excitatory response by increasing subthreshold conductance in CA1 hippocampal pyramidal cells. The identity of the receptor mediating this response was not conclusively identified, but resembled the 5-HT1C receptor.
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PMID:5-Hydroxytryptamine increases excitability of CA1 hippocampal pyramidal cells. 158 62

Several developments in serotonin neuropharmacology have implications for psychiatric disorders and have already begun to impact their treatment. Selective inhibitors of serotonin uptake, which enhance serotonergic function by preventing the removal of serotonin from the synaptic cleft via the membrane transporter, have been introduced for the treatment of depression and may be effective in other disorders. Precursor loading can increase serotonin concentrations in the synaptic cleft, and tryptophan--which has been available in health food stores and drug stores--had become increasingly used for self-medication of depression, insomnia, and premenstrual syndrome. Conversion to serotonin is not the major metabolic pathway for tryptophan, and large increases in other tryptophan metabolites (such as quinolinic acid, a substance that is excitotoxic at high concentrations) accompany small increases in extracellular serotonin. The recent epidemic of the eosinophilia-myalgia syndrome associated with tryptophan now appears due to a trace contaminant in the product from a single manufacturer. A major advance in serotonin pharmacology has been the elucidation of serotonin receptor heterogeneity. At least seven receptor subtypes (5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT2, 5-HT3, 5-HT4) have been identified in brain. Direct-acting agonists and antagonists can have selective affinity for specific receptor subtypes. Selective activation of 5-HT1A receptors seems to cause anxiolytic and possibly antidepressive effects. Selective antagonists of 5-HT2 or 5-HT3 receptors may be useful in treating anxiety and schizophrenia. Drugs that enhance serotonergic function suppress aggression in animals, but the specific receptor subtypes involved are not known. The advances being made in serotonin pharmacology will help define the role of this brain neurotransmitter in psychiatric and other disorders and can be expected to lead to further therapeutic advances.
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PMID:Role of serotonin in therapy of depression and related disorders. 167 51

The effects of serotonin (5-hydroxytryptamine; 5-HT) on the cardiovascular system are complex. These effects, consisting of bradycardia or tachycardia, hypotension or hypertension, and vasodilation or vasoconstriction are mediated by three main sets of receptors called 5-HT1-like, 5-HT2, and 5-HT3. In addition, recent findings suggest the participation of a putative 5-HT4 receptor. Though selective 5-HT1A receptor agonists can lower heart rate (and arterial blood pressure), 5-HT usually lowers heart rate by eliciting an initial short-lasting hypotension due to bradycardia (von Bezold-Jarisch-like reflex) via 5-HT3 receptors located on sensory vagal nerve endings in the heart. Once this bradycardia reflex is suppressed--for example, during deep anesthesia, vagotomy, or spinal section--5-HT can increase heart rate in different species by a variety of mechanisms. Myocardial 5-HT1-like, 5-HT2, and 5-HT4 receptors appear to be involved in the cat, rat, and pig, respectively. 5-HT-induced tachycardia in the dog and rabbit is due mainly to release of catecholamines and involves 5-HT2 receptors on the adrenal medulla and 5-HT3 receptors on postganglionic cardiac sympathetic nerve fibers. Recently, 5-HT3 receptors also have been implicated in the 5-HT-induced tachycardia in the conscious dog. The blood pressure response to 5-HT is usually triphasic and consists of a von Bezold-Jarisch-like reflex, a middle pressor phase, and a longer-lasting hypotension. The pressor response is a consequence of vasoconstriction mediated via 5-HT2 receptors; however, vasoconstriction in the dog saphenous vein and cephalic arteries and arteriovenous anastomoses is due to stimulation of 5-HT1-like receptors. The depressor response exclusively involves 5-HT1-like receptors located at four different sites: (a) central nervous system (decrease in sympathetic and increase in vagal nervous activity), (b) sympathetic nerve terminals (reduction of transmitter release), (c) vascular smooth muscle (vasodilatation), and (d) vascular endothelium (release of a relaxant factor, probably nitric oxide). Arteriolar dilatation, together with the constriction of arteriovenous anastomoses, leads to an increase in nutrient (tissue; capillary) blood flow. The 5-HT1-like receptors are heterogeneous in nature; however, apart from the resemblance of the central nervous system 5-HT1-like receptor causing hypotension and bradycardia to the 5-HT1A binding subtype, the relationship of the other 5-HT1-like receptors to 5-HT1 binding subtypes is still debatable.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cardiovascular effects of serotonin agonists and antagonists. 170 84

While it had no effect on the resting tension of mouse tracheal segments, 5-HT (10(-8)-10(-4) M) potentiated concentration dependently the contractions induced by electrical field stimulation (EFS). The maximal potentiation was 105 +/- 38% and the EC50 value was 1.4 +/- 0.6 x 10(-6) M (n = 6). The responsiveness of mouse trachea to acetylcholine was not altered by 5-HT (10(-5) M). The 5-HT1A,B antagonist pindolol (10(-6) M), the combined 5-HT2 and 5-HT1C receptor antagonist, ketanserin (10(-6) M), or the combined 5-HT1 and 5-HT2 receptor antagonist, methysergide (10(-6) M), all partially inhibited the effect of 5-HT on the twitch responses. Blockade of 5-HT3 receptors by GR 38032F (10(-6) M) did not affect the potentiation by 5-HT. Antagonism of 5-HT3 and 5-HT4 receptors by ICS 205,930 (3 x 10(-6) M) increased the potentiation of the twitch responses by 5-HT, this was probably due to a decrease of the baseline EFS-induced twitch response by ICS 205,930. Alkylation of the 5-HT2 receptor by phenoxybenzamine (3 x 10(-7) M) treatment did not significantly affect the potentiation of the twitch responses by 5-HT. The beta-adrenoceptor antagonist, timolol (10(-6) M), and the alpha-adrenoceptor antagonist, phentolamine (10(-6) M), did not influence the potentiation of the twitch responses by 5-HT, excluding the involvement of the adrenergic system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:5-HT1-like receptors mediate potentiation of cholinergic nerve-mediated contraction of isolated mouse trachea. 179 65

Four major families of serotonin (5-hydroxytryptamine; 5-HT) receptors have been identified: 5-HT1, 5-HT2, 5-HT3 and 5-HT4. At this time, there is a general consensus that the 5-HT1 family can be further subdivided into 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT1P subpopulations. In addition, there are several other populations of less well-defined 5-HT receptors. The purpose of this presentation is to discuss 5-HT receptor nomenclature and the agents that are commonly used to investigate each receptor population in as much as it will serve to provide background for the remainder of the symposium. There is presently available an abundance of serotonergic agents; however, these agents are only semiselective, and none can be considered truly selective for a particular population of 5-HT receptors. As useful as these agents have been for the identification and characterization of 5-HT receptors, there remains a need for the development of new, more selective ligands.
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PMID:Serotonin receptors and their ligands: a lack of selective agents. 181 55

To date, there have been at least eight different receptors for the neurotransmitter serotonin (5-HT) identified in the central nervous system. These receptors fall into four pharmacological classes: 5-HT1, 5-HT2, 5-HT3 and 5-HT4. The 5-HT1 class has been shown to contain at least four pharmacologically distinct subtypes, 5-HT1A-D. Of these, cDNAs encoding the 5-HT1A and 5-HT1C receptors have been previously characterized. We now report the cloning and expression of a rat brain cDNA encoding another member of the 5-HT1 receptor family. Transient expression of this clone demonstrated high-affinity binding of [3H]5-HT with a pharmacological profile corresponding to that of the 5-HT1B subtype: 5-CT, 5-HT greater than propranolol greater than methysergide greater than rauwolscine greater than 8-OH-DPAT. In situ hybridization revealed expression of cognate mRNA within cells of the dorsal and median raphe nuclei, consistent with previous reports that the 5-HT1B receptor acts as an autoreceptor on 5-HT terminals in this species. mRNA expression was also detected in cells within the CA1 region of hippocampus, striatum, layer 4 of cortex and in the cerebellum, suggesting a previously unrecognized post-synaptic role for the 5-HT1B receptor.
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PMID:Molecular cloning and characterization of a rat brain cDNA encoding a 5-hydroxytryptamine1B receptor. 183 57

Hippocampal pyramidal neurons of the CA1 region express 5-hydroxytryptamine (serotonin, 5-HT) receptors which, upon activation, elicit a slow membrane depolarization and a decrease in the calcium-activated afterhyperpolarization present in these cells. Previous electrophysiological studies have shown that this receptor(s) exhibits a pharmacological profile similar to that of the 5-HT1p, 5-HT3 and 5-HT4 subtypes. In the present study, intracellular recordings in rat brain slices were used in order to examine the effects of a variety of compounds that distinguish between these receptor subtypes. Administration of 5-HT in the presence of a 5-HT1A receptor antagonist elicited a depolarization and a concentration-dependent reduction in the amplitude of the afterhyperpolarization. These effects were mimicked by 5-methoxytryptamine and 5-carboxyamidotryptamine but not by 2-methyl-5-HT or phenylbiguanide. Administration of the benzamides BRL 24924, zacopride and cisapride blocked the responses to 5-HT with micromolar affinity although, in a small proportion of the cells tested, BRL 24924 was found to exhibit some agonist activity. This suggests that these compounds function as weak partial agonists in the rat hippocampus. These results establish clear differences between the 5-HT receptor(s) mediating the depolarization and reduction in the afterhyperpolarization in the hippocampus and the 5-HT3 and 5-HT1p receptors and suggest its classification in the 5-HT4 class. Thus, 5-HT4 receptors appear capable of mediating slow excitatory responses to 5-HT in the brain.
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PMID:5-Hydroxytryptamine4-like receptors mediate the slow excitatory response to serotonin in the rat hippocampus. 204 27

5-Hydroxytryptamine (5-HT) receptors were originally subclassified into the subtypes M and D based on the findings that 5-HT contracted the guinea-pig ileum by two different mechanisms: (a) directly by an effect on receptors located on smooth muscles (via D receptors), and (b) indirectly by an effect on neuronal receptors (M receptors), the activation of which caused acetylcholine release. With the introduction of radioligand-binding studies and the development of more selective 5-HT agonists and antagonists, it rapidly became apparent that this subclassification is an oversimplification, and it is now accepted that at least three, possibly four main families of 5-HT receptors exist: 5-HT1, 5-HT2, 5-HT3 and possibly 5-HT4 receptors. Furthermore, 5-HT1 receptors are not a homogeneous class, but are subdivided further into four subtypes: 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D. Whether 5-HT2 and 5-HT3 receptors are also a heterogeneous class of receptors is still a matter of controversy. Besides the differences in specific agonists and antagonists, 5-HT-receptor subtypes seem to differ also in their signal-transduction mechanisms. 5-HT1 receptors (with the exception of 5-HT1C) are coupled to adenylate cyclase, predominantly in an inhibitory fashion, but 5-HT1-mediated activation of adenylate cyclase has been also described. 5-HT2 receptors (and 5-HT1C) are coupled to PI turnover, while 5-HT3 receptors appear to be coupled directly to fast ion channels. On the other hand, 5-HT4 receptors couple obviously in an excitatory fashion to adenylate cyclase.
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PMID:5-Hydroxytryptamine-receptor subtypes. 213 74


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