Indole-3-piperazinyl derivatives: novel chemical class of 5-HT(6) receptor antagonists

N₁-Arylsulfonyl-3-piperazinyl indole derivatives were designed and identified as a novel class of 5-HT₆ receptors ligands. All the compounds have high affinity and antagonist activity towards 5-HT₆ receptor. The compound 7a (K_i = 3.4 nM, functional assay IC₅₀ = 310 nM) shows enhanced cognitive effect when tested in NORT and Morris water maze models. Synthesis, SAR and PK profile of these novel compounds constitute the subject matter of this Letter.     

Design,synthesis and preliminary screening of novel 3-(2-N,N-dimethylaminoethylthio) indole derivatives as potential 5-HT6 receptor ligands

The synthesis and potential 5-hydroxytryptamine₆ receptor (5-HT₆R) antagonist activity of a novel series of N-arylsulfonyl-3-(2-N,N-dimethylaminoethylthio) indoles has been reported. The molecular modeling, synthesis and in-vitro radioligand binding data of this series are discussed. The present article describes 37 derivatives of the title series. It was observed that the increased side-chain length with the insertion of a sulfur atom did not lead to the loss of binding affinity of these compounds, although the affinities were reduced. The compounds exhibited moderate affinity and selectivity to human 5-HT₆ receptors.     

Discovery of PF-00217830: aryl piperazine napthyridinones as D2 partial agonists for schizophrenia and bipolar disorder

The synthesis and structure-activity relationship (SAR) of a novel series of aryl piperazine napthyridinone D₂ partial agonists is described. Our goal was to optimize the affinities for the D₂, 5-HT_2A and 5-HT_1A receptors, such that the D₂/5-HT_2A ratio was greater than 5 to ensure maximal occupancy of these receptors when the D₂ occupancy reached efficacious levels. This strategy led to identification of PF-00217830 (2) with robust inhibition of sLMA (MED = 0.3 mg/kg) and DOI-induced head twitches in rats (31% and 78% at 0.3 and 1 mg/kg) with no catalepsy observed at the highest dose tested (10 mg/kg).     

Synthesis and preliminary screening of novel N-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}acetamides as potential atypical antipsychotic agents

A series of N-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}acetamides were synthesized as prospective novel atypical antipsychotic agents. Microwave irradiation of acetyl glycine (I) with substituted piperazines in the presence of DCC in DMF for about 3-5 min gave the titled compounds (P:1-7). All the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. D₂ antagonism studies were performed using the climbing mouse assay model and 5-HT_2A antagonism studies were performed using quipazine induced head twitches in mice. Among the synthesized compounds P4 was found to be the most active compound.     

The serotonin 5-HT1D receptor: A progress review

Most of the known neurotransmitters interact with more than one type of receptor. Some of them even dispose of receptor subtypes to exert their actions. Serotonin, far from being an exception to that, possesses at least 3 classes of receptors, which have all been reported to be heterogeneous, although convincing data only exist for the 5-HT₁ class. This name has been proposed in 1979, two years before the introduction of A and B in the nomenclature to account for the observed heterogeneity of these cites. The 5-HT_1C receptor subtype was first described in 1984 and the last member of the family, named 5-HT_1D, was characterized in 1987. The pharmacological profiles, the signal transducing systems and the anatomical localizations, both at the regional and cellular levels, of all these subtypes have been investigated and possible functions have been proposed for each of them. Moreover, last and most definitive demonstration of the subtype individuality, the gene or complementary DNA coding for the 5-HT_1A and 5-HT_1C (and 5-HT₂) receptors have been cloned and sequenced. Such data are still missing for 5-HT_1D (and 5-HT_1B) receptors, but will certainly be provided in the next few years. However and waiting for this decisive clue, the characterization of the 5-HT_1D subtype leaves no doubt concerning its significance as a functional 5-HT receptor. This review will concentrate on the characteristics of this subtype of 5-HT receptor.Abbreviations 5-CT 5-carboxamidotryptamine - 5-MeOT 5-methoxy-tryptamine - 5-MeODMT N,N-dimethyl-5-methoxytryptamine - 8-OH-DPAT 8-hydroxy-2[di-n-propylamino]tetralin - CYP cyanopindolol - DHE dihydroergotamine - DOI 2,5-dimethoxy-4-iodophenylisopropylamine - DP-5-CT N,N-dipropyl 5-carboxamidotryptamine - ICPY 2-iodo-cyanopindolol - mCPP m-chloro-phenyl-piperazine - TFMPP m-trifluoro-methyl-phenyl-piperazine - E_MAX Maximal effect - EC₅₀ Half maximal effective concentration - K_D Dissociation constant - K_B Antagonist dissociation constant     

Design, synthesis and evaluation of bicyclic benzamides as novel 5-HT1F receptor agonists

Several fused bicyclic systems have been investigated to serve as the core structure of potent and selective 5-HT_1F receptor agonists. Replacement of the indole nucleus in 2 with indazole and ‘inverted’ indazole provided more potent and selective 5-HT_1F receptor ligands. Indoline and 1,2-benzisoxazole systems also provided potent 5-HT_1F receptor agonists, and the 5-HT_1A receptor selectivity of the indoline- and 1,2-benzisoxazole-based 5-HT_1F receptor agonists could be improved with modification of the benzoyl moiety of the benzamides. Through these studies, we found that the inherent geometries of the templates, not the nature of hybridization of the linking atom, were important for the 5-HT_1F receptor recognition.     

Stimulation of dopamine D1 receptor improves learning capacity in cooperating cleaner fish

Accurate contextual decision-making strategies are important in social environments. Specific areas in the brain are tasked to process these complex interactions and generate correct follow-up responses. The dorsolateral and dorsomedial parts of the telencephalon in the teleost fish brain are neural substrates modulated by the neurotransmitter dopamine (DA), and are part of an important neural circuitry that drives animal behaviour from the most basic actions such as learning to search for food, to properly choosing partners and managing decisions based on context. The Indo-Pacific cleaner wrasse Labroides dimidiatus is a highly social teleost fish species with a complex network of interactions with its ‘client’ reef fish. We asked if changes in DA signalling would affect individual learning ability by presenting cleaner fish two ecologically different tasks that simulated a natural situation requiring accurate decision-making. We demonstrate that there is an involvement of the DA system and D₁ receptor pathways on cleaners'' natural abilities to learn both tasks. Our results add significantly to the growing literature on the physiological mechanisms that underlie and facilitate the expression of cooperative abilities.     

Two transmembrane Cys residues are involved in 5-HT4 receptor dimerization

The 5-HT₄ receptor (5-HT₄R) belongs to the G-protein-coupled receptor (GPCR) family and is of considerable interest for the development of new drugs to treat gastrointestinal diseases and memory disorders. The 5-HT₄R exists as a constitutive dimer but its molecular determinants are still unknown. Using co-immunoprecipitation and Bioluminescence Resonance Energy Transfer (BRET) techniques, we show here that 5-HT₄R homodimerization but not 5-HT₄R-β₂ adrenergic receptor (β₂AR) heterodimerization is largely decreased under reducing conditions suggesting the participation of disulfide bonds in 5-HT₄R dimerization. Molecular modeling and protein docking experiments identified four cysteine (Cys) residues potentially involved in the dimer interface through intramolecular or intermolecular disulfide bonds. We show that disulfide bridges between Cys112 and Cys145 located within TM3 and TM4, respectively, are of critical importance for 5-HT₄R dimer formation. Our data suggest that two disulfide bridges between two transmembrane Cys residues are involved in the dimerization interface of a GPCR.     

1-(Arylsulfonyl)-2,3-dihydro-1H-quinolin-4-one derivatives as 5-HT(6) serotonin receptor ligands

Piperazinyl derivatives of 1-(arylsulfonyl)-2,3-dihydro-1H-quinolin-4-ones have been identified with high binding affinities for 5-HT₆ receptor. In particular, 2-methyl-5-(N-methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one (8g) exhibits high binding affinity toward 5-HT₆ (IC₅₀ = 8 nM) receptor with good selectivity over other serotonin and dopamine receptors.     

Dopamine D2 and D4 receptor heteromerization and its allosteric receptor-receptor interactions

Dopamine D₂ and D₄ receptors partially codistribute in the dorsal striatum and appear to play a fundamental role in complex behaviors and motor function. The discovery of D₂R–D_4.xR (D_4.2R, D_4.4R or D_4.7R) heteromers has been made in cellular models using co-immunoprecipitation, in situ Proximity Ligation Assays and BRET¹ techniques with the D₂R and D_4.7R receptors being the least effective in forming heteromers. Allosteric receptor–receptor interactions in D₂R–D_4.2R and D₂R–D_4.4 R heteromers were observed using the MAPK assays indicating the existence of an enhancing allosteric receptor–receptor interaction in the corresponding heteromers between the two orthosteric binding sites. The bioinformatic predictions suggest the existence of a basic set of common triplets (ALQ and LRA) in the two participating receptors that may contribute to the receptor–receptor interaction interfaces.     

The effect of the selective 5-HT(3) receptor agonist on ferret gut motility

The effect of the selective 5-hydroxytryptamine (5-HT)(3) receptor agonist YM-31636 (2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole monofumarate) on gut motility of fed ferrets was investigated. YM-31636 (0.1 mg/kg p.o.) induced a giant migrating contraction (GMC)-like, high-amplitude, ungrouped colonic contraction although it did not change the basal colonic motility pattern. This GMC-like contraction was always accompanied by defecation. Both GMC-like contraction and defecation were inhibited with the selective 5-HT(3) receptor antagonist ramosetron. YM-31636 affected gastric, duodenal and ileal motility pattern only slightly. These results suggest that 5-HT(3) receptor agonists such as YM-31636 are useful in treating constipation since they facilitate GMC-like contractions and defecation without undesired changes in gut motility pattern.     

Quinoxalin-2-carboxamides: synthesis and pharmacological evaluation as serotonin type-3 (5-HT3) receptor antagonists

A series of quinoxalin-2-carboxamides were designed as per the pharmacophoric requirements of 5-HT₃ receptor antagonists and synthesized by condensing the carboxylic group of quinoxalin-2-carboxylic acid with various amines in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole. The structures of the synthesized compounds were confirmed by physical and spectroscopic data. The carboxamides were evaluated for their 5-HT₃ receptor antagonisms in longitudinal muscle-myenteric plexus preparation from guinea pig ileum against 5-HT₃ agonist, 2-methy-5-HT. All the synthesized compounds showed 5-HT₃ receptor antagonism, (4-benzylpiperazin-1-yl)(quinoxalin-2-yl)methanone was the most potent compound among this series.     

Involvement of 1,25D3-MARRS (membrane associated, rapid response steroid-binding), a novel vitamin D receptor, in growth inhibition of breast cancer cells

In addition to classical roles in calcium homeostasis and bone development, 1,25 dihydroxyvitamin D₃ [1,25(OH)₂D₃] inhibits the growth of several cancer types, including breast cancer. Although cellular effects of 1,25(OH)₂D₃ traditionally have been attributed to activation of a nuclear vitamin D receptor (VDR), a novel receptor for 1,25(OH)₂D₃ called 1,25D₃-MARRS (membrane-associated, rapid response steroid-binding) protein was identified recently. The purpose of this study was to determine if the level of 1,25D₃-MARRS expression modulates 1,25(OH)₂D₃ activity in breast cancer cells.Relative levels of 1,25D₃-MARRS protein in MCF-7, MDA MB 231, and MCF-10A cells were estimated by real-time RT-PCR and Western blotting. To determine if 1,25D₃-MARRS receptor was involved in the growth inhibitory effects of 1,25(OH)₂D₃ in MCF-7 cells, a ribozyme construct designed to knock down 1,25D₃-MARRS mRNA was stably transfected into MCF-7 cells. MCF-7 clones in which 1,25D₃-MARRS receptor expression was reduced showed increased sensitivity to 1,25(OH)₂D₃ ( IC₅₀ 56 ± 24 nM) compared to controls (319 ± 181 nM; P < 0.05). Reduction in 1,25D₃-MARRS receptor lengthened the doubling time in transfectants treated with 1,25(OH)₂D₃. Knockdown of 1,25D₃-MARRS receptor also increased the sensitivity of MCF-7 cells to the vitamin D analogs KH1060 and MC903, but not to unrelated agents (all-trans retinoic acid, paclitaxel, serum/glucose starvation, or the isoflavone, pomiferin). These results suggest that 1,25D₃-MARRS receptor expression interferes with the growth inhibitory activity of 1,25(OH)₂D₃ in breast cancer cells, possibly through the nuclear VDR. Further research should examine the potential for pharmacological or natural agents that modify 1,25D₃-MARRS expression or activity as anticancer agents.     

Synthesis and evaluation of pyridazinone-phenethylamine derivatives as selective and orally bioavailable histamine H3 receptor antagonists with robust wake-promoting activity

A series of pyridazinone-phenethylamine derivatives with moderate to low nanomolar affinity for rat and human H(3)R are described. These analogs exhibited excellent selectivity and metabolic stability, with acceptable rat pharmacokinetic properties. In vivo, 7 and 11 demonstrated potent H(3)R functional antagonism in the rat dipsogenia model and robust wake-promoting activity in the rat electroencephalogram/electromyography (EEG/EMG) model.     

Caffeine decreases vitamin D receptor protein expression and 1,25(OH)2D3 stimulated alkaline phosphatase activity in human osteoblast cells

Of the various risk factors contributing to osteoporosis, dietary/lifestyle factors are important. In a clinical study we reported that women with caffeine intakes >300 mg/day had higher bone loss and women with vitamin D receptor (VDR) variant, tt were at a greater risk for this deleterious effect of caffeine. However, the mechanism of how caffeine effects bone metabolism is not clear. 1,25-Dihydroxy vitamin D₃ (1,25(OH)₂D₃) plays a critical role in regulating bone metabolism. The receptor for 1,25(OH)₂D₃, VDR has been demonstrated in osteoblast cells and it belongs to the superfamily of nuclear hormone receptors. To understand the molecular mechanism of the role of caffeine in relation to bone, we tested the effect of caffeine on VDR expression and 1,25(OH)₂D₃ mediated actions in bone. We therefore examined the effect of different doses of caffeine (0.2, 0.5, 1.0 and 10 mM) on 1,25(OH)₂D₃ induced VDR protein expression in human osteoblast cells. We also tested the effect of different doses of caffeine on 1,25(OH)₂D₃ induced alkaline phosphatase (ALP) activity, a widely used marker of osteoblastic activity. Caffeine dose dependently decreased the 1,25(OH)₂D₃ induced VDR expression and at concentrations of 1 and 10 mM, VDR expression was decreased by about 50–70%, respectively. In addition, the 1,25(OH)₂D₃ induced alkaline phosphatase activity was also reduced at similar doses thus affecting the osteoblastic function. The basal ALP activity was not affected with increasing doses of caffeine. Overall, our results suggest that caffeine affects 1,25(OH)₂D₃ stimulated VDR protein expression and 1,25(OH)₂D₃ mediated actions in human osteoblast cells.     

Proterguride, a highly potent dopamine receptor agonist promising for transdermal administration in Parkinson's disease: interactions with alpha(1)-, 5-HT(2)- and H(1)-receptors

Dopamine receptor agonists play an important role in the treatment of Parkinson's disease and hyperprolactinemic conditions. Proterguride (n-propyldihydrolisuride) was already reported to be a highly potent dopamine receptor agonist, thus its action at different non-dopaminergic monoamine receptors, alpha(1A/1B/1D), 5-HT(2A/2B)- and histamine H(1), was investigated using different functional in vitro assays. The drug behaved as an antagonist at alpha(1)-adrenoceptors without the ability to discriminate between the subtypes (pA(2) values: alpha(1A) 7.31; alpha(1B) 7.37; alpha(1D) 7.35) and showed antagonistic properties at the histamine H(1) receptor. In contrast, at serotonergic receptors (5-HT(2A), 5-HT(2B)) proterguride acted as a partial agonist. The drug stimulated 5-HT(2A) receptors of rat tail artery in lower concentrations than 5-HT itself but failed to evoke comparable efficacy (proterguride: pEC(50) 8.34, E(max) 53% related to the maximum response to 5-HT; 5-HT: pEC(50) 7.03). Agonism at 5-HT(2B) receptors is presently considered to be involved in drug-induced valvular heart disease. Activation of 5-HT(2B) receptors in porcine pulmonary arteries by proterguride (pEC(50) 7.13, E(max) 49%; E(max) (5-HT) 69%), however, occurred at concentrations much higher than plasma concentrations achieving dopaminergic efficacy in humans. The results are discussed focussing on the relevance of action at 5-HT(2B) receptors as well as their significance for a transdermal administration of proterguride. Since it is well accepted that pulsatile dopaminergic stimulation is associated with treatment-related motor complications in the dopaminergic therapy of Parkinson's disease, the transdermal route of administration is of great clinical interest due to the possibility to achieve constant plasma concentrations.     

Synthesis and biological evaluation of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential antiplatelet agents

Despite the substantial clinical success of aspirin and clopidogrel in secondary prevention of ischemic stroke, up to 40% of patients remain resistant to the available antiplatelet treatment. Therefore, there is an urgent clinical need to develop novel antiplatelet agents with a novel mechanism of action. Recent studies revealed that potent alpha 2B-adrenergic receptor (alpha 2B-ARs) antagonists could constitute alternative antiplatelet therapy. We have synthesized a series of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential alpha 2B receptor antagonists. The most potent compound 3, effectively inhibited the platelet-aggregation induced both by collagen and ADP/adrenaline with IC₅₀ of 26.9?μM and 20.5?μM respectively. Our study confirmed that the alpha 2B-AR antagonists remain an interesting target for the development of novel antiplatelet agents with an alternative mechanism of action.     

Synthesis and pharmacological evaluation of novel 1- and 8-substituted-3-furfuryl xanthines as adenosine receptor antagonists

The synthesis of an important set of 3-furfurylxanthine derivatives is described. Binding affinities were determined for rat A₁ and human A_2A, A_2B and A₃ receptors. Several of the 3-furfuryl-7-methylxanthine derivatives showed moderate-to-high affinity at human A_2B receptors, the most active compound (10d) having a K_i of 7.4 nM for hA_2B receptors, with selectivities over rA₁ and hA_2A receptors up to 14-fold and 11-fold, respectively. Affinities for hA₃ receptors were very low for all members of the set.     

Dopamine acts through a D2-like receptor on a jellyfish motor neuron

Summary Dopamine, which is present in nerve-rich tissues of the hydromedusa Polyorchis penicillatus, produces membrane hyperpolarization in identified motor neurons from this jellyfish. In this study we demonstrate that the inhibitory action of dopamine is mediated by conventional drug-receptor interactions which are reversible, saturable and specific. When 10 M dopamine was applied by micro-spritzing onto voltage-clamped (holding potential, –20 mV), cultured swimming motor neurons, an outward current of about 1 nA was evoked. Using this technique, we established a potency order for several amines: dopaminenorepinephrine>tyramine >octopamine>-phenylethylamine. Dopamine is effective at concentrations betweeen 1 × 10^-8 and 1 × 10^-3 M. Several dopamine receptor blockers such as fluphenazine, haloperidol and spiperone reduced the dopamine-induced current in a concentration-dependent manner. Although propranolol, a -adrenergic blocker, reduced the dopamine response and SKF 83566, a D₁ blocker, increased the response, it appears that the dopamine receptors in these jellyfish neurons share pharmacological properties with mammalian D₂ dopamine receptors.