- Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT1AReceptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile
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Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT1A receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential "signaling fingerprints"that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of "serotonergic syndrome". Both compounds showed promising developability properties. The presented 5-HT1A receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.
- Sniecikowska, Joanna,Gluch-Lutwin, Monika,Bucki, Adam,Wi?ckowska, Anna,Siwek, Agata,Jastrzebska-Wiesek, Magdalena,Partyka, Anna,Wilczyńska, Daria,Pytka, Karolina,Latacz, Gniewomir,Przejczowska-Pomierny, Katarzyna,Wyska, El?bieta,Weso?owska, Anna,Paw?owski, Maciej,Newman-Tancredi, Adrian,Kolaczkowski, Marcin
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supporting information
p. 10946 - 10971
(2020/11/09)
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- Amino Acid Hot Spots of Halogen Bonding: A Combined Theoretical and Experimental Case Study of the 5-HT7 Receptor
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A computational approach combining a structure-activity relationship library of halogenated and the corresponding unsubstituted ligands (called XSAR) with QM-based molecular docking and binding free energy calculations was used to search for amino acids frequently targeted by halogen bonding (hot spots) in a 5-HT7R as a case study. The procedure identified two sets of hot spots, extracellular (D2.65, T2.64, and E7.35) and transmembrane (C3.36, T5.39, and S5.42), which were further verified by a synthesized library of halogenated arylsulfonamide derivatives of (aryloxy)ethylpiperidines. It was found that a halogen bond formed between T5.39 and a bromine atom at 3-position of the aryloxy fragment caused the most remarkable, 35-fold increase in binding affinity for 5-HT7R when compared to the nonhalogenated analog. The proposed paradigm of halogen bonding hot spots was additionally verified on D4 dopamine receptor showing that it can be used in rational drug design/optimization for any protein target.
- Kurczab, Rafa,Canale, Vittorio,Sataa, Grzegorz,Zajdel, Pawea,Bojarski, Andrzej J.
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supporting information
p. 8717 - 8733
(2018/10/02)
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- DOPAMINE D2 RECEPTOR LIGANDS
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The present invention relates to novel dopamine D2 receptor ligands. The invention further relates to functionally-biased dopamine D2 receptor ligands and the use of these compounds for treating or preventing central nervous system and systemic disorders associated with dysregulation of dopaminergic activity. The present invention relates to novel compounds that modulate dopamine D2 receptors. In particular, compounds of the present invention show functional selectivity at the dopamine D2 receptors and exhibit selectivity downstream of the D2 receptors, on the 0- arrestin pathway and/or on the cAMP pathway.
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Page/Page column 126; 127
(2016/07/05)
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- DOPAMINE D2 RECEPTOR LIGANDS
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The present invention relates to novel dopamine D2 receptor ligands. The invention further relates to functionally-biased dopamine D2 receptor ligands and the use of these compounds for treating or preventing central nervous system and systemic disorders associated with dysregulation of dopaminergic activity.
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Page/Page column 119; 123
(2016/07/05)
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- New serotonin 5-HT1A receptor agonists endowed with antinociceptive activity in vivo
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We report the synthesis of new compounds 4-35 based on two different openings (A and B) of the chromane ring present in the previously identified 5-HT1A receptor (5-HT1AR) ligand 3. The synthesized compounds were assessed for binding affinity, selectivity, and functional activity at the 5-HT1AR. Selected candidates resulting from B opening were also evaluated for their potential antinociceptive effect in vivo and pharmacokinetic properties in vitro. Analogue 19 [2-(4-{[2-(2-ethoxyphenoxy) ethyl]amino}butyl)tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione] has been characterized as a high-affinity and potent 5-HT1AR agonist (K i = 2.3 nM; EC50 = 19 nM). Pharmacokinetic studies indicated that compound 19 displays a good metabolic stability in human liver microsomes (t1/2 ~ 3 h and CLint = 3.5 mL/min/kg, at 5 μM), and a low level of protein binding (25%, at 5 μM). Interestingly, 19 (3 mg/kg, ip, and 30 mg/kg, po) caused significant attenuation of formalin-induced behavior in early and late phases of the mouse intradermal formalin test of pain, and this in vivo effect was reversed by the selective 5-HT1AR antagonist WAY-100635. Thus, the new 5-HT1AR agonist identified in this work, 19, exhibits oral analgesic activity, and the results herein represent a step toward identifying new therapeutics for the control of pain.
- Valhondo, Margarita,Marco, Isabel,Martín-Fontecha, Mar,Vázquez-Villa, Henar,Ramos, José A.,Berkels, Reinhard,Lauterbach, Thomas,Benhamú, Bellinda,López-Rodríguez, María L.
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supporting information
p. 7851 - 7861
(2013/11/06)
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- Synthesis and anticonvulsant evaluation of some N-substituted phthalimides
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Two series of phthalimides - one possessing an N-phenoxyalkyl moiety substituted at position 3 or 4 of the phenyl ring (1-9) and the other of N-alkenyl or alkinyl phthalimides (10-18) - were synthesized, evaluated for anticonvulsant activity and had their in silico lipophilicity estimated using computer programs. The anticonvulsant activity of phthalimides containing an unsaturated substituent at the phthalimide nitrogen was superior to that of the N-phenoxyalkyl phthalimides. Alkinyl derivative 10 emerged as the most active (in MES and ScMet tests) of all the compounds tested. A correlation between anticonvulsant activity and in silico estimated lipophilicity was not observed.
- Wiecek, Malgorzata,Kiec-Kononowicz, Katarzyna
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experimental part
p. 249 - 257
(2009/12/24)
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- Piperidine variations in search for non-imidazole histamine H3 receptor ligands
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Synthesis and biological evaluation of the novel histamine H3 receptor ligands is described. Two series of ethers (aliphatic and aromatic) have been prepared by four different methods. Compounds were evaluated for their affinities at recombinant human H3 receptor stably expressed in CHO cells. The ethers show from low to moderate in vitro affinities in nanomolar concentration range. The most potent compound was the 1-[3-(4-tert-butylphenoxy)propyl]-4-piperidino-piperidine 16 (hH3R Ki = 100 nM). Several members of the new series investigated under in vivo conditions, proved to be inactive.
- Lazewska, Dorota,Kuder, Kamil,Ligneau, Xavier,Schwartz, Jean-Charles,Schunack, Walter,Stark, Holger,Kiec-Kononowicz, Katarzyna
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experimental part
p. 8729 - 8736
(2009/04/06)
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- Oximic derivatives with a fungicide activity
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A description follows of oximic derivatives with a fungicide activity, for agricultural use, having the formula (I): STR1 wherein: A, B, D, are N, or =C--G; G is H, halogen, NO2, CN, --COOR4, C1 -C6 (halo)alkyl R1, R2, R4 and R5, are C1 -C6 (halo)alkyl; R3 is H, C1 -C6 (halo)alkyl or --COOR5 ; W is C2 -C10 alkylene; L represents O or S; Y represents phenyl, naphthyl, heterocycle, substituted alkyl.
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- Oximic derivatives with fungicidal activity
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A description follows of oximic derivatives with a fungicide activity, for agricultural use, having the formula (I): wherein: A, B, D, are N, or =C-G; G is H, halogen, NO2, CN, -COOR4, C1-C6 (halo)alkyl R1, R2, R4 and R5, are C1-C6 (halo)alkyl; R3 is H, C1-C6 (halo)alkyl or -COOR5; W is C2-C10 alkylene; L represents O or S; Y represents phenyl, naphthyl, heterocycle, substituted alkyl.
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- Nitrogen-containing heterocyclic compounds with antifungal action, use and a composition thereof
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Nitrogen-containing heterocyclic compounds endowed with antifungal action, which have the general formula: STR1 wherein: Ar=phenyl, optionally substituted with halogens, (C1 -C3)-alkyls, (C1 -C3)-haloalkyls, (C
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- Fungicidal heterocyclic nitrogen compounds
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Fungicidal heterocyclic nitrogen compounds are described. Said compounds have the general formula: wherein:, Ar is optionally substituted phenyl or optionally substituted pyridyl;, K, X and Z represent O or S:, B1 and B2 are C1
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