- Characterization of potent and selective antagonists at postsynaptic 5- HT(1A) receptors in a series of N4-substituted arylpiperazines
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Benzocycloalkyl and benzocycloalkenyl moities linked, directly or via an alkyl chain, to oxygen-bearing heteroarylpiperazines were synthesized, in an attempt to obtain potent and selective antagonists at postsynaptic 5-HT(1A) receptors. From the numerous arylpiperazines described in the literature, 1- (2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (3a) was chosen as a model of an arylpiperazine in view of its selectivity for 5-HT(1A) receptors versus α1- , α2-, and β-adrenergic receptors, as well as dopamine D1 and D2 receptors. Two other closely-related arylpiperazines, 1-(1,5-benzodioxepin- 6-yl)piperazine (3b) and 1-(benzofuran-7-yl)piperazine (3c), were also examined in this study. All compounds showed high affinity at 5-HT(1A) sites (8.10 ≤ pK(i)s ≤ 9.35), and the majority behaved as antagonists in viva in blocking the hypothermia induced by the 5-HT(1A) agonist 8-OH-DPAT in the absence of a marked effect alone at equivalent doses. An in vivo evaluation of dopamine D2 receptor antagonist properties revealed that the majority of compounds was devoid of activity at this site, in marked contrast to BMY 7378 which displayed virtually no selectivity far 5-HT(1A) versus dopamine D2 receptors. Moreover, six compounds of the present series, 8, 10, 11, 14, 25, and, 37, showed > 10-fold selectivity in vitro for 5-HT(1A) versus α1- adrenergic receptors. Compound 14 displayed an optimal compromise between potency (pK(i) = 8.75), marked antagonist activity, and selectivity toward α1-adrenergic (81-fold) and dopamine D2 (195-fold) receptors. These characteristics clearly distinguish 14 from previously-reported ligands such as the postsynaptic 5-HT(1A) antagonist BMY 7378 and the weak partial agonist NAN 190 which, in contrast to the compounds of this series, belong to the well-exemplified class of imido derivatives of (o-methoxyphenyl)piperazines. The availability of 14 (S 15535) should facilitate the further elucidation of the functional role and potential therapeutic significance of 5-HT(1A) receptors.
- Peglion,Canton,Bervoets,Audinot,Brocco,Gobert,Le Marouille-Girardon,Millan
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- Regio- And Enantioselective Iridium-Catalyzed Amination of Alkyl-Substituted Allylic Acetates with Secondary Amines
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Robust air-stable cyclometalated π-allyliridium C,O-benzoates modified by (S)-tol-BINAP catalyze the reaction of secondary aliphatic amines with racemic alkyl-substituted allylic acetates to furnish products of allylic amination with high levels of enantioselectivity. Complete branched regioselectivities were observed despite the formation of more highly substituted C-N bonds.
- Jung, Woo-Ok,Yoo, Minjin,Migliozzi, Madyson M.,Zbieg, Jason R.,Stivala, Craig E.,Krische, Michael J.
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supporting information
p. 441 - 445
(2021/12/27)
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- COMPOUNDS
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The present invention relates to compounds of Formula I as defined herein, and salts and solvates thereof. (I) The present invention also relates to pharmaceutical compositions comprising compounds of Formula(I), and to compounds of Formula(I) for use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which inhibition of a RAS-effector protein-protein interaction is implicated.
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Paragraph 00266; 00163; 00299
(2019/08/12)
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- Discovery of G Protein-Biased D2 Dopamine Receptor Partial Agonists
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Biased ligands (also known as functionally selective ligands) of G protein-coupled receptors are valuable tools for dissecting the roles of G protein-dependent and independent signaling pathways in health and disease. Biased ligands have also been increasingly pursued by the biomedical community as promising therapeutics with improved efficacy and reduced side effects compared with unbiased ligands. We previously discovered first-in-class β-arrestin-biased agonists of dopamine D2 receptor (D2R) by extensively exploring multiple regions of aripiprazole, a balanced D2R agonist. In our continuing efforts to identify biased agonists of D2R, we unexpectedly discovered a G protein-biased agonist of D2R, compound 1, which is the first G protein-biased D2R agonist from the aripiprazole scaffold. We designed and synthesized novel analogues to explore two regions of 1 and conducted structure-functional selectivity relationship (SFSR) studies. Here we report the discovery of 1, findings from our SFSR studies, and characterization of novel G protein-biased D2R agonists.
- Chen, Xin,McCorvy, John D.,Fischer, Matthew G.,Butler, Kyle V.,Shen, Yudao,Roth, Bryan L.,Jin, Jian
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p. 10601 - 10618
(2016/12/16)
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- FUNCTIONALLY SELECTIVE LIGANDS OF DOPAMINE D2 RECEPTORS
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The present invention relates to novel functionally selective ligands of dopamine D2 receptors, including agonists, antagonists, and inverse agonists. The invention further relates to the use of these compounds for treating central nervous system disorders related to D2 receptors.
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- Piperazine-piperidine antagonists and agonists of the 5-HT1A receptor
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The present invention relates to novel piperazine-piperidine compounds. The compounds are useful as 5-HT1A binding agents, particularly as 5-HT1A receptor antagonists and agonists. These compounds are useful in treating central nervous system disorders, such as cognition disorders, anxiety disorders, depression and sexual dysfunction.
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Page/Page column 48
(2010/11/25)
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- Trisubstituted-oxazole derivatives as serotonin ligands
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Compounds of the formula are useful for the treatment of anxiety, depression and related CNS disorders and other conditions such as the treatment of alcohol and drug withdrawal, sexual dysfunction and Alzheimer's disease.
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- Piperazine derivatives as therapeutic agents
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Substituted piperazine compounds of formula I STR1 in which HET is a substituted pyrazole, imidazole or 1,2,4-triazole have utility in the treatment of central nervous system disorders, for example depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, senile dementia, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders and anorexia, cardiovascular and cerebrovascular disorders, non-insulin dependent diabetes mellitus, hyperglycaemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress, prostatic hypertrophy, and spasticity.
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- N-((phenyl, benzodioxinyl or N-heteroarylpiperazinyl)alkyl)-N-(N-heteroaryl)substituted carboxamides
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Piperazine derivatives of formula I and their pharmaceutically acceptable acid addition salts are 5-HT1A binding agents, particularly 5-HT1A antagonists and may be used, for example, as anxiolytics. In the formula A is C2-4 alkylene chain optionally substituted by lower alkyl, Z is oxygen or sulphur, R is hydrogen or lower alkyl, R1 is a mono or bicyclic aryl or heteroaryl radical, R2 is a mono or bicyclic heteroaryl radical and R3 is hydrogen or a specified radical such as lower alkyl, cycloalkyl, aryl, heteroaryl or optionally substituted amino.
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- Synthesis of arylpiperazines via palladium-catalysed aromatic amination reactions of bromoarenes with N-tert-butoxycarbonylpiperazine
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Reaction of a series of bicyclic bromoarenes with N-tert- butoxycarbonylpiperazine (N-Boc-piperazine) under palladium-catalysed coupling conditions followed by routine removal of the Boc group with trifluoroacetic acid in dichloromethane gave the corresponding arylpiperazines in moderate to good yield.
- Kerrigan, Frank,Martin, Claire,Thomas, Gerard H.
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p. 2219 - 2222
(2007/10/03)
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- PIPERAZINE DERIVATIVES AS 5-HT ANTAGONISTS
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This invention concerns compounds of formula (I) STR1 where A is a C 1 or C 2 alkylene chain optionally substituted by lower alkyl; Z is a bicyclic oxygen-containing aryl radical (e.g. 2,3-dihydro-1,4-benzodioxin-5-yl); R is hydrogen or lower alkyl; R 1 is aryl or aryl(lower)alkyl; R 2 is hydrogen or lower alkyl; and R 3 is hydrogen, an alkyl group of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms; cycloalkyl(lower)alkyl, aryl or aryl(lower)alkyl or R. sup.2 and R 3 together with the nitrogen atom to which they are both attached represent a saturated heterocyclic ring which may contain a further hetero atom, and the pharmaceutically acceptable acid addition salts thereof. The compounds are 5-HT 1A-antagonists which may be used, for example, in treating anxiety.
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