Synthesis and structure-activity relationships of a series of benzazepine derivatives as 5-HT2C receptor agonists

To identify potent and selective 5-HT(2C) receptor agonists, a series of novel benzazepine derivatives were synthesized, and their structure-activity relationships examined. The compounds were evaluated for their 5-HT(2C), 5-HT(2A), and 5-HT(2B) receptor binding affinity and intrinsic activity for the 5-HT(2C) and 5-HT(2A) receptors. Among these compounds, 6,7-dichloro-2,3,4,5-tetrahydro-1H-3-benzazepine (6) was effective in a rat penile erection model when administered po, which is a symptom of the serotonin syndrome reflecting 5-HT(2C) receptor activation. Moreover, compound 6 was characterized as a partial agonist of 5-HT(2A) receptors; therefore, it had little effect on the cardiovascular system.     

Discovery and SAR of new benzazepines as potent and selective 5-HT(2C) receptor agonists for the treatment of obesity

We report on the synthesis, biological evaluation and structure-activity relationships for a series of 3-benzazepine derivatives as 5-HT(2C) receptor agonists. The compounds were evaluated in functional assays measuring [3H] phosphoinositol turnover in HEK-293 cells transiently transfected with h5-HT(2C), h5-HT(2A) or h5-HT(2B) receptors. Several compounds are shown to be potent and selective 5-HT(2C) receptor agonists, which decrease food intake in a rat feeding model.     

The identification of pyrimidine-diazabicyclo[3.3.0]octane derivatives as 5-HT2C receptor agonists

The 5-HT2C receptor has been implicated in the regulation of appetite. As such, small molecule agonists to this receptor may serve as novel therapies to combat obesity. We describe here the identification, synthesis, and SAR of a 5-HT2C agonist from a unique pyrimidine-diazabicyclo[3.3.0]octane series. This compound displayed good potency at the 5-HT2C receptor, modest selectivity relative to other 5-HT2 receptors, and was efficacious in an acute feeding study in rats.     

SAR of psilocybin analogs: discovery of a selective 5-HT 2C agonist

An SAR study of psilocybin and psilocin derivatives reveals that 1-methylpsilocin is a selective agonist at the h5-HT(2C) receptor. The corresponding phosphate derivative, 1-methylpsilocybin, shows efficacy in an animal model for obsessive-compulsive disorder, as does 4-fluoro-N,N-dimethyltryptamine. These results suggest a new area for development of novel 5-HT(2C) agonists with applications for drug discovery.     

Synthesis and structure-activity relationships of a series of substituted 2-(1H-furo[2,3-g]indazol-1-yl)ethylamine derivatives as 5-HT2C receptor agonists

A series of novel indazole derivatives were synthesized, and their structure-activity relationships examined in order to identify potent and selective 5-HT2C receptor agonists. Among these compounds, (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine (YM348) had a good in vitro profile, that is, high agonistic activity to the human 5-HT2C receptor subtype (EC50 = 1.0 nM) and high selectivity over 5-HT2A receptors. This compound was also effective in a rat penile erection model when administered p.o.     

Serotonergic regulation of blood glucose levels in the crayfish, Procambarus clarkii: site of action and receptor characterization

The present study investigated the site of action of 5-hydroxytryptamine (5-HT) and pharmacologically characterized the receptors involved in regulating blood glucose levels in the crayfish, Procambarus clarkii. Injection of 5-HT into intact animals increased glucose levels in a dose-dependent manner. In contrast, 5-HT failed to elicit a hyperglycemic response in eyestalk-ablated animals. Effects of several 5-HT receptor agonists and antagonists were examined. 5-CT, oxymetazoline (both 5-HT(1) receptor agonists) and alpha-methyl-5-HT (a 5-HT(2) receptor agonist), but not 1-phenylbiguanide, m-CPBG (both 5-HT(3) receptor agonists), or RS 67333 (a 5-HT(4) receptor agonist), induced hyperglycemic responses in a dose-dependent manner. In addition, 8-OH-DPAT (a 5-HT(1A) receptor agonist), L-694,247 (a 5-HT(1B/1D) receptor agonist), and DOI (a 5-HT(2A) receptor agonist) were effective in significantly increasing the glucose levels, whereas both BW 723C86 (a 5-HT(2B) receptor agonist) and m-CPP (a 5-HT(2C) receptor agonist) were ineffective. Finally, ketanserin (a 5-HT(2A) receptor antagonist), but not p-MPPF (a 5-HT(1A) receptor antagonist), GR 55562 (a 5-HT(1B/1D) receptor antagonist), SB 206553 (a 5-HT(2B/2C) receptor antagonist), or tropisetron (a 5-HT(3) receptor antagonist), was able to block 5-HT-induced hyperglycemia. The combined results support the hypothesis that 5-HT exerts its hyperglycemic effect by enhancing the release of hyperglycemic factor(s) from the eyestalks, and suggest that 5 HT-induced hyperglycemia is mediated by 5-HT(1)- and 5-HT(2)-like receptors.     

High-affinity agonist binding correlates with efficacy (intrinsic activity) at the human serotonin 5-HT2A and 5-HT2C receptors: evidence favoring the ternary complex and two-state models of agonist action

Many modern models of receptor-G protein function assume that there is a direct relationship between high-affinity agonist binding and efficacy. The validity of this assumption has been recently questioned for the serotonin 5-HT2A receptor. We examined the intrinsic activities of various ligands in activating phosphoinositide hydrolysis and measured their respective binding affinities to the high- and low-affinity states of the 5-HT2C (VNV isoform) and 5-HT(2A) receptors. Ligand binding affinities for the high-affinity state of the receptors were determined using 1-(4-[125I]iodo-2,5-dimethoxyphenyl)2-aminopropane, whereas [3H]mesulergine and N-[3H]methylspiperone were used, in the presence of excess guanine nucleotide [guanosine 5'-O-(3-thiotriphosphate)], to define binding to the low-affinity state of the 5-HT2C and 5-HT2A receptors, respectively. Antagonists labeled the high- and low-affinity states of each receptor with comparable affinities. Previously identified inverse agonists of the 5-HT2C receptor behaved as silent antagonists in our systems even when the receptor was overexpressed at a relatively high density. In contrast, the ability of agonists to bind differentially to the high- and low-affinity states of the 5-HT2A and 5-HT2C receptors was highly correlated (r2 = 0.86 and 0.96, respectively) with their intrinsic activities. These data suggest that high-affinity agonist states can account for agonist efficacy at human 5-HT2A or 5-HT2C receptors without the need for considering additional transition or active states of the receptor-ligand complex. The procedure described herein may expedite drug discovery efforts by predicting intrinsic activities of ligands solely from ligand binding assays.     

Influence of serotonergic transmission anD postsynaptic 5-HT2C action on the feeding behavior of Coturnix japonica (Galliformes: Aves).

We investigated the role of 5-HT2C receptors and serotonergic transmission in the feeding behavior control of quails. Administration of serotonin releaser, fenfluramine (FEN) and 5-HT2C agonists, mCPP and MK212, 1.0 and 3.3 mg/Kg induced significant inhibition of food intake in previously fasted fowls (0.71 +/- 0.18 g and 0.47 +/- 0.2 g; 0.49 +/- 0.22 g and 0.48 +/- 0.29 g; 0.82 +/- 0.13 g and 0.71 +/- 0.16 g, respectively). Control groups ranged from 2.89 +/- 0.21 g to 2.97 +/- 0.22 g, 60 min after reintroduction of food, P < 0.0001). Similar results were obtained with normally fed quails. Both serotonin releaser and 5-HT2C agonists, in a 3.3 mg/Kg dose, induced hypophagy (FEN, 0.78 +/- 0.08 g; mCPP, 0.89 +/- 0.07 g; MK212, 1.25 +/- 0.17 g vs. controls, 2.05 +/- 0.12 g, 120 min after food was presented, P < 0.0001 to P < 0.01). Previous administration of 5-HT2C antagonist, LY53857 (5.0 mg/Kg) blocked the hypophagic response induced by 5-HT2C agonists 60 min after food was reintroduced. Current data show a modulatory role of serotonin release and postsynaptic 5-HT2C receptors in the feeding behavior of quails.     

The agonists of I-A serotoninergic receptors restore in rats behavior impaired by L-dihydroxyphenylalanine

The ability of selective and nonselective 5-HT1A agonists, nondirect 5-HT agonists and 5-HT2 antagonists influence on the L-DOPA-disturbed rats behaviour were studied. The results indicate that agonists 5-HT1A like receptors largely than 5-HT2,3 agonists, 5-HT2 antagonists and nondirect 5-HT agonists promote restoration of the L-DOPA disturbed escape behaviour in acute stress situation.     

Unique ionotropic receptors for D-aspartate are a target for serotonin-induced synaptic plasticity in Aplysia californica

The non-L-glutamate (L-Glu) receptor component of D-aspartate (D-Asp) currents in Aplysia californica buccal S cluster (BSC) neurons was studied with whole cell voltage clamp to differentiate it from receptors activated by other well-known agonists of the Aplysia nervous system and investigate modulatory mechanisms of D-Asp currents associated with synaptic plasticity. Acetylcholine (ACh) and serotonin (5-HT) activated whole cell excitatory currents with similar current voltage relationships to D-Asp. These currents, however, were pharmacologically distinct from D-Asp. ACh currents were blocked by hexamethonium (C6) and tubocurarine (D-TC), while D-Asp currents were unaffected. 5-HT currents were blocked by granisetron and methysergide (MES), while D-Asp currents were unaffected. Conversely, while (2S,3R)-1-(Phenanthren-2-carbonyl)piperazine-2,3-dicarboxylic acid(PPDA) blocked D-Asp currents, it had no effect on ACh or 5-HT currents. Comparison of the charge area described by currents induced by ACh or 5-HT separately from, or with, D-Asp suggests activation of distinct receptors by all 3 agonists. Charge area comparisons with L-Glu, however, suggested some overlap between L-Glu and D-Asp receptors. Ten minute exposure to 5-HT induced facilitation of D-Asp-evoked responses in BSC neurons. This effect was mimicked by phorbol ester, suggesting that protein kinase C (PKC) was involved.     

Identification of 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT2C receptor agonists

Synthesis and evaluation of the activity of new 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT(2C) receptor agonists are described. Appropriately substituted, several analogs displayed selectivity against the other 5-HT(2) receptor subtypes of 1 order of magnitude or more. Selectivity was improved for several compounds versus the lead 1, increasing the therapeutic interest in this series of 5-HT(2C) receptor agonists.     

Pyrrolo[3,2,1-ij]quinoline derivatives, a 5-HT2c receptor agonist with selectivity over the 5-HT2a receptor: potential therapeutic applications for epilepsy and obesity

A series of pyrrolo[3,2,1-ij]quinoline derivatives was synthesized, evaluated for their activity against the 5-HT2c and 5-HT2a, receptors and found to be agonists at 5-HT2c with selectivity over 5-HT2a.     

Potential Mechanisms Involved in the Negative Coupling Between Serotonin 5-HT1A Receptors and Carbachol-Stimulated Phosphoinositide Turnover in the Rat Hippocampus

Serotonin 5-HT1A receptors have been reported to be negatively coupled to muscarinic receptor-stimulated phosphoinositide turnover in the rat hippocampus. In the present study, we have investigated further the pharmacological specificity of this negative control and attempted to elucidate the mechanism whereby 5-HT1A receptor activation inhibits the carbachol-stimulated phosphoinositide response in immature or adult rat hippocampal slices. Various 5-HT1A receptor agonists were found to inhibit carbachol (10 microM)-stimulated formation of total inositol phosphates in immature rat hippocampal slices with the following rank order of potency (IC50 values in nM): 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (11) greater than ipsapirone (20) greater than gepirone (120) greater than RU 24969 (140) greater than buspirone (560) greater than 1-(m-trifluoromethylphenyl)piperazine (1,500) greater than methysergide (5,644); selective 5-HT1B, 5-HT2, and 5-HT3 receptor agonists were inactive. The potency of the 5-HT1A receptor agonists investigated as inhibitors of the carbachol response was well correlated (r = 0.92) with their potency as inhibitors of the forskolin-stimulated adenylate cyclase in guinea pig hippocampal membranes. 8-OH-DPAT (10 microM) fully inhibited the carbachol-stimulated formation of inositol di-, tris-, and tetrakisphosphate but only partially antagonized (-40%) inositol monophosphate production. The effect of 8-OH-DPAT on carbachol-stimulated phosphoinositide turnover was not prevented by addition of tetrodotoxin (1 microM), by prior destruction of serotonergic afferents, by experimental manipulations causing an increase in cyclic AMP levels (addition of 10 microM forskolin), or by changes in membrane potential (increase in K+ concentration or addition of tetraethylammonium). Prior intrahippocampal injection of pertussis toxin also failed to alter the ability of 8-OH-DPAT to inhibit the carbachol response. Carbachol-stimulated phosphoinositide turnover in immature rat hippocampal slices was inhibited by the protein kinase C activators phorbol 12-myristate 13-acetate (10 microM) and arachidonic acid (100 microM). Moreover, the inhibitory effect of 8-OH-DPAT on the carbachol response was blocked by 10 microM quinacrine (a phospholipase A2 inhibitor) but not by BW 755C (100 microM), a cyclooxygenase and lipoxygenase inhibitor. These results collectively suggest that 5-HT1A receptor activation inhibits carbachol-stimulated phosphoinositide turnover by stimulating a phospholipase A2 coupled to 5-HT1A receptors, leading to arachidonic acid release. Arachidonic acid could in turn activate a gamma-protein kinase C with as a consequence an inhibition of carbachol-stimulated phosphoinositide turnover. This inhibition may be the consequence of a phospholipase C phosphorylation and/or a direct effect on the muscarinic receptor.(ABSTRACT TRUNCATED AT 400 WORDS)     

1,2,3,4-tetrahydroisoquinoline derivatives: a new class of 5-HT1A receptor ligands

Three series of new N-substituted 1,2,3,4-tetrahydroisoquinolines with 2-, 3-, and 4-membered alkyl chains (a, b, and c, respectively) were synthesized, and the effect of some structural modifications on their 5-HT1A receptor affinities and functional properties was discussed. It was found that the volume of the terminal amide substituent was a crucial parameter which determined 5-HT1A receptor affinities of the tested compounds, while the in vivo activity seemed to depend on both the R-volume and the length of a hydrocarbon chain. It was demonstrated that the most active ligands behaved like agonists or partial agonists at postsynaptic 5-HT1A receptors.     

Effects of acute and chronic administration of the serotonin1A agonist buspirone on serotonin synthesis in the rat brain

The effects of acute and chronic administration of buspirone, a serotonin 5-HT1A agonist, on the 5-HT synthesis rates in various rat brain structures were investigated using alpha-[14C]methyl-L-tryptophan (alpha-[14C]MTrp) and an autoradiographic method. In the acute treatment study, buspirone (10 mg/kg) was injected subcutaneously 30 min before alpha-[14C]MTrp administration (30 microCi over 2 min) into a femoral vein. In the chronic treatment study, buspirone was given in a sustained fashion (10 mg/kg/day) for 14 days using an osmotic minipump implanted subcutaneously. Rats were killed 60 and 150 min after alpha-[14C]MTrp administration (two-time point method). A single dose of buspirone induced a significant decrease of 5-HT synthesis throughout the brain with the exception of the pineal body. However, the chronic treatment with buspirone did not induce significant differences in 5-HT synthesis in the brain. There was no significant difference in plasma free tryptophan concentration between any of the groups. The unaltered 5-HT synthesis rates in the chronic treatment study likely reflect a normalization of this parameter due to a desensitization of 5-HT1A autoreceptors on the cell body of 5-HT neurons, which has been previously shown to occur following long-term treatment with 5-HT1A agonists.     

Serotonin 5-ht2c receptor agonists: potential for the treatment of obesity

Obesity continues to be a burgeoning health problem worldwide. Before their removal from the market, fenfluramine and the more active enantiomer dexfenfluramine were considered to be among the most effective of weight loss agents. Much of the weight loss produced by fenfluramine was attributed to the direct activation of serotonin 5-HT(2C) receptors in the central nervous system via the desmethyl-metabolite of fenfluramine, norfenfluramine. Norfenfluramine, however, is non-selective, activating additional serotonin receptors, such as 5-HT(2A) and 5-HT(2B), which likely mediated the heart valve hypertrophy seen in many patients. Development of highly selective 5-HT(2C) agonists may recapitulate the clinical anti-obesity properties observed with fenfluramine while avoiding the significant cardiovascular and pulmonary side effects.     

Pyrrolo(iso)quinoline derivatives as 5-HT(2C) receptor agonists

A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported. The analogue which showed the highest 5-HT(2C) binding affinity (27, 1.6nM) was found to be successful in reducing food intake in rats.     

Regulatory molecules for the 5-HT3 receptor ion channel gating system

Substituted benzoxazole derivatives which possess a nitrogen-containing heterocycle at C2 are selective partial agonists of the 5-HT(3) receptor. Alteration of substituents on the benzoxazole nucleus affords both agonist-like and antagonist-like compounds, and uniquely modifies the function of the 5-HT(3) receptor ion channel gating system. SAR and corroborative computational docking study for these partial agonists successfully explained structure and function of the 5-HT(3) receptor.