- Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist
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To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
- Moritz, Amy E.,Free, R. Benjamin,Weiner, Warren S.,Akano, Emmanuel O.,Gandhi, Disha,Abramyan, Ara,Keck, Thomas M.,Ferrer, Marc,Hu, Xin,Southall, Noel,Steiner, Joseph,Aubé, Jeffrey,Shi, Lei,Frankowski, Kevin J.,Sibley, David R.
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p. 5526 - 5567
(2020/06/17)
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- 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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- 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
(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 118; 119
(2016/07/05)
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- Development of unsymmetrical dyads as potent noncarbohydrate-based inhibitors against human β-N-acetyl-D-hexosaminidase
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Human β-N-acetyl-D-hexosaminidase has gained much attention due to its roles in several pathological processes and been considered as potential targets for disease therapy. A novel and efficient skeleton, which was an unsymmetrical dyad containing naphthalimide and methoxyphenyl moieties with an alkylamine spacer linkage as a noncarbohydrate-based inhibitor, was synthesized, and the activities were valuated against human β-N-acetyl-D- hexosaminidase. The most potent inhibitor exhibits high inhibitory activity with Ki values of 0.63 μM. The straightforward synthetic manners of these unsymmetrical dyads and understanding of the binding model could be advantageous for further structure optimization and development of new therapeutic agents for Hex-related diseases.
- Guo, Peng,Chen, Qi,Liu, Tian,Xu, Lin,Yang, Qing,Qian, Xuhong
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p. 527 - 531
(2013/07/26)
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- Diether derivatives of homo- or substituted piperidines as non-imidazole histamine H3 receptor ligands
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Synthesis and biological activities of a series of homo- or substituted piperidine unsymmetrical diethers are described. The novel compounds were evaluated for histamine H3 receptor binding affinities at recombinant human H3 receptor
- Lazewska, Dorota,Kuder, Kamil,Ligneau, Xavier,Camelin, Jean-Claude,Schunack, Walter,Stark, Holger,Kiec-Kononowicz, Katarzyna
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experimental part
p. 3037 - 3042
(2009/09/30)
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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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- Novel cyclic amide derivatives
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Novel compounds represented by the following formula (I) that act as a ligand to sigma receptor/binding cite and a medicament comprising the same as an active ingredient: wherein X represents an alkyl group, an aryl group, a heterocyclic group or the like; Q represents a group represented by —CH2—, —CO—, —O—, —CH(OR7)— or the like wherein R7 represents a hydrogen atom, an alkyl group or the like; n represents an integer of from 0 to 5; R1 and R2 each represent a hydrogen atom, an alkyl group or the like; B represents either of the following groups: wherein R3, R4, R5, and R6 each represent a hydrogen atom, a halogen atom, an alkoxyl group or the like; m represents 1 or 2; and the ring of: represents an aromatic heterocyclic ring.
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- A simple modification of the known preparation procedure of 2-Phenoxyethyl bromides providing high yields
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A modification of preparation method was developed for synthesis of a number of 1-bromo-2-phenoxyethanes from 1,2-dibromoethanes and sodium phenolates in two-phase water-organic system with or without addition of triethylbenzylammonium chloride as phase-transfer catalyst. Addition of NaOH in two portions for transforming phenols into phenolates ensured high yields (60-80%) of phenoxylation products.
- Slyn'ko,Tormyshev
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p. 254 - 257
(2007/10/03)
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