WAY-163909 [(7bR, 10aR)-1,2,3,4,8,9,10,10a-Octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole], a Novel 5-Hydroxytryptamine 2C Receptor-Selective Agonist with Anorectic Activity

Using solution or solid-phase synthesis we prepared the cholecystokinin fragment Boc-CCK-7 (Boc-Tyr-(SO3-.Na+)-Met-Gly-Trp-Met-Asp-PheNH2) and its four analogues in which the methionine moiety (Met) in the carboxy-terminal part is replaced by tert-leucine (Tle) or neopentylglycine (Neo) residue or D-enantiomers of these non-coded amino acids. These structural modifications led to reduction of the studied biological activities (gall bladder contraction, anorectic activity, analgetic and sedation activity) of all prepared analogues except Boc[Neo5]-CCK-7 which, being less analgetically active, retains full gall bladder and sedation activity of CCK-8. Moreover, its anorectic activity is substantially higher (400%). This analogue is very interesting particularly for its selectively increased (4x) anorectic effect compared with that of CCK-8.

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Role of Satb1 and Satb2 Transcription Factors in the Glutamate Receptors Expression and Ca2+ Signaling in the Cortical Neurons In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms22115968 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5968

Author(s):

Egor A. Turovsky ◽

Maria V. Turovskaya ◽

Evgeniya I. Fedotova ◽

Alexey A. Babaev ◽

Viktor S. Tarabykin ◽

...

Keyword(s):

Transcription Factors ◽

Nmda Receptor ◽

Cortical Neurons ◽

Target Genes ◽

Cortical Cell ◽

Inhibitory System ◽

Selective Agonist ◽

Genes Encoding ◽

Deficient Mice

Transcription factors Satb1 and Satb2 are involved in the processes of cortex development and maturation of neurons. Alterations in the expression of their target genes can lead to neurodegenerative processes. Molecular and cellular mechanisms of regulation of neurotransmission by these transcription factors remain poorly understood. In this study, we have shown that transcription factors Satb1 and Satb2 participate in the regulation of genes encoding the NMDA-, AMPA-, and KA- receptor subunits and the inhibitory GABA(A) receptor. Deletion of gene for either Satb1 or Satb2 homologous factors induces the expression of genes encoding the NMDA receptor subunits, thereby leading to higher amplitudes of Ca2+-signals in neurons derived from the Satb1-deficient (Satb1fl/+ * NexCre/+) and Satb1-null mice (Satb1fl/fl * NexCre/+) in response to the selective agonist reducing the EC50 for the NMDA receptor. Simultaneously, there is an increase in the expression of the Gria2 gene, encoding the AMPA receptor subunit, thus decreasing the Ca2+-signals of neurons in response to the treatment with a selective agonist (5-Fluorowillardiine (FW)). The Satb1 deletion increases the sensitivity of the KA receptor to the agonist (domoic acid), in the cortical neurons of the Satb1-deficient mice but decreases it in the Satb1-null mice. At the same time, the Satb2 deletion decreases Ca2+-signals and the sensitivity of the KA receptor to the agonist in neurons from the Satb1-null and the Satb1-deficient mice. The Satb1 deletion affects the development of the inhibitory system of neurotransmission resulting in the suppression of the neuron maturation process and switching the GABAergic responses from excitatory to inhibitory, while the Satb2 deletion has a similar effect only in the Satb1-null mice. We show that the Satb1 and Satb2 transcription factors are involved in the regulation of the transmission of excitatory signals and inhibition of the neuronal network in the cortical cell culture.

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Low Basal CB2R in Dopamine Neurons and Microglia Influences Cannabinoid Tetrad Effects

International Journal of Molecular Sciences ◽

10.3390/ijms21249763 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9763

Author(s):

Qing-Rong Liu ◽

Ana Canseco-Alba ◽

Ying Liang ◽

Hiroki Ishiguro ◽

Emmanuel S. Onaivi

Keyword(s):

Cortical Neurons ◽

Cannabinoid Receptors ◽

Dynamic Range ◽

Conditional Knockout ◽

Dopamine Neurons ◽

In Vivo Studies ◽

Mouse Strains ◽

Genotypic Differences ◽

Mrna Levels ◽

Selective Agonist

There are two well-characterized cannabinoid receptors (CB1R and CB2R and other candidates): the central nervous system (CNS) enriched CB1R and peripheral tissue enriched CB2R with a wide dynamic range of expression levels in different cell types of human tissues. Hepatocytes and neurons express low baseline CB1R and CB2R, respectively, and their cell-type-specific functions are not well defined. Here we report inducible expression of CB1R in the liver by high-fat and high sugar diet and CB2R in cortical neurons by methamphetamine. While there is less controversy about hepatocyte CB1R, the presence of functional neuronal CB2R is still debated to date. We found that neuron CB2R basal expression was higher than that of hepatocyte CB1R by measuring mRNA levels of specific isoform CB2A in neurons isolated by fluorescence-activated cell sorting (FACS) and CB1A in hepatocytes isolated by collagenase perfusion of liver. For in vivo studies, we generated hepatocyte, dopaminergic neuron, and microglia-specific conditional knockout mice (Abl-Cnr1Δ, Dat-Cnr2Δ, and Cx3cr1-Cnr2Δ) of CB1R and CB2R by crossing Cnr1f/f and Cnr2f/f strains to Abl-Cre, Dat-Cre, and Cx3cr1-Cre deleter mouse strains, respectively. Our data reveals that neuron and microglia CB2Rs are involved in the “tetrad” effects of the mixed agonist WIN 55212-2, CB1R selective agonist arachidonyl-2′-chloroethylamide (ACEA), and CB2R selective agonist JWH133. Dat-Cnr2Δ and Cx3cr1-Cnr2Δ mice showed genotypic differences in hypomobility, hypothermia, analgesia, and catalepsy induced by the synthetic cannabinoids. Alcohol conditioned place preference was abolished in DAT-Cnr2Δ mice and remained intact in Cx3cr1-Cnr2Δ mice in comparison to WT mice. These Cre-loxP recombinant mouse lines provide unique approaches in cannabinoid research for dissecting the complex endocannabinoid system that is implicated in many chronic disorders.

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Further pharmacological evaluation of a novel synthetic peptide bradykinin B2 receptor agonist

Biological Chemistry ◽

10.1515/hsz-2012-0295 ◽

2013 ◽

Vol 394 (3) ◽

pp. 353-360 ◽

Cited By ~ 9

Author(s):

Martin Savard ◽

Julie Labonté ◽

Céléna Dubuc ◽

Witold Neugebauer ◽

Pedro D’Orléans-Juste ◽

...

Keyword(s):

Knockout Mice ◽

Synthetic Peptide ◽

Receptor Agonist ◽

Rabbit Lung ◽

Hypotensive Action ◽

Duration Of Action ◽

Selective Agonist ◽

Comparable Magnitude

Abstract We recently identified a novel human B2 receptor (B2R) agonist [Hyp3,Thi5,NChg7,Thi8]-bradykinin (NG291) with greater in vitro and in vivo potency and duration of action than natural bradykinin (BK). Here, we further examined its stability and selectivity toward B2R. The hypotensive, antithrombotic, and profibrinolytic functions of NG291 relative to BK and its analogue ([Hyp3,Thi5,(4-Me)Tyr8(ΨCH2NH)Arg9]-BK) (RMP-7) were also tested. Contraction assays using isolated mouse stomachs (containing kinin B1R, B2R, and kininase I- and II-like activities) showed that NG291 is a more potent contractant than BK and is inhibited by HOE-140 (B2R antagonist) but unaffected by R954 (B1R antagonist), whereas both decreased the potency of BK. In stomach tissues from B2R knockout mice, BK maintained its activity via B1R, whereas NG291 had no contractile effect, indicating that it was selective for B2R. Unlike BK, NG291 was not degraded by rabbit lung ACE. Comparing intravenously administered BK and NG291 revealed that NG291 exhibited more potent and prolonged hypotensive action and greater antithrombotic and profibrinolytic activities. These effects were of comparable magnitude to RMP-7 and were absent in B2R knockout mice. We concluded that NG291 is a novel biostable B2R-selective agonist that may prove suitable for investigating the (pre)clinical cardioprotective efficacy of B2R activation.

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