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Defining Structure-Functional Selectivity Relationships (SFSR) for a Class of Non-Catechol Dopamine D1 Receptor Agonists

G protein-coupled receptors (GPCRs) are capable of downstream signaling through distinct noncanonical pathways such as beta-arrestins in addition to the canonical G protein-dependent pathways. GPCR ligands that differentially activate the downstream signaling pathways are termed functionally selective or biased ligands. A class of novel non-catechol G protein-biased agonists of the dopamine D1 receptor (D1R) was recently disclosed. We conducted the first comprehensive structure-functional selectivity relationship study measuring GS and beta-arrestin2 recruitment activities focused on four regions of this scaffold, resulting in over 50 analogs with diverse functional selectivity profiles. Some compounds became potent full agonists of beta-arrestin2 recruitment, while others displayed enhanced GS bias compared to the starting compound. Pharmacokinetic testing of an analog with an altered functional selectivity profile demonstrated excellent blood-brain barrier penetration. This study provides novel tools for studying ligand bias at D1R and paves the way for developing the next generation of biased D1R ligands.

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Reference:
Isoquinoline – Wikipedia,
Isoquinoline | C9H1388N – PubChem

 

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Biphenyl-based diaminophosphine oxides as air-stable preligands for the nickel-catalyzed kumada-tamao-corriu coupling of deactivated aryl chlorides, fluorides, and tosylates

A cooperative couple: Cooperative bimetallic activation of C-F and C-O bonds gave rise to easy coupling with aryl fluorides and tosylates. Novel air- and moisture-stable diaminophosphine oxides derived from 1,1?-biphenyl-2, 2?-diamine proved to be versatile preligands for the nickel-catalyzed cross-coupling of aryl Grignard reagents with a variety of deactivated aryl chlorides, fluorides, and tosylates (see scheme). Copyright

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Isoquinoline – Wikipedia,
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NOVEL TETRADENTATE PLATINUM COMPLEXES

Novel phosphorescent tetradentate platinum (II) compounds comprising a twisted aryl group are provided. Also provided are novel phosphorescent tetradentate platinum (II) compounds comprising an imidazo[1,2-f]phenanthridine moiety. The compounds may be used in organic light emitting devices to provide improved device efficiency, line shape and lifetime.

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Isoquinoline – Wikipedia,
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Bright orange/red-emitting rhodium(iii) and iridium(iii) complexes: Tridentate N^C^N-cyclometallating ligands lead to high luminescence efficiencies

Rhodium(iii) complexes rarely display strong phosphorescence, in contrast to well-known iridium(iii) complexes with cyclometallating ligands. This study shows how 1,3-bis(1-isoquinolyl)benzene cyclometallates to Rh(iii) through N^C^N-coordination to give complexes with unprecedented phosphorescence quantum yields at room temperature. Their highly emissive Ir(iii) analogues are also described.

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Isoquinoline – Wikipedia,
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Rh(III)-Catalyzed [4 + 2] Self-Annulation of N-Vinylarylamides

An efficient rhodium(III)-catalyzed self-annulation of N-vinylarylamide has been developed. This reaction features a simple system and good reactivity with complete regioselectivity. The protocol provides easy access to an aminal incorporated dihydroisoquinolinone, which proved to be a versatile synthetic synthon. The kinetic isotope effect experiments showed that C-H activation is the rate-limiting step, and competition studies revealed the annulation exhibits a strong self-recognition mode. In addition, a seven-membered rhodacycle species was isolated and established as the key reaction intermediate.

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Isoquinoline – Wikipedia,
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New luminescent cyclometalated iridium(III) complexes containing fluorinated phenylisoquinoline-based ligands: Synthesis, structures, photophysical properties and DFT calculations

Two new fluorinated phenylisoquinoline-based iridium(III) complexes, [Ir(f2piq)2(bipy)][PF6] (3a) and [Ir(fmpiq)2(bipy)][PF6] (3b) (f2piq = 1-(2,4-difluorophenyl)isoquinoline, fmpiq = 1-(4-fluoro-2-methylphenyl)isoquinoline, bipy = 2,2?-bipyridine), have been synthesized and fully characterized. Single crystal X-ray diffraction study has been undertaken on complexes 3a and 3b, which show that each adopts the distorted octahedral coordination geometry with the cis-C,C? and trans-N,N? configuration. The photoluminescence spectra of 3a and 3b exhibit yellow and orange emission maxima at 584 and 600 nm, respectively. The frontier molecular orbital diagrams and the lowest-energy electronic transitions of 3a-3b have been calculated with density functional theory (DFT) and time-dependent DFT (TD-DFT). The absorption and emission spectra of complex 3b is red-shifted relative to those of complex 3a, as a consequence of the nature of the methyl group.

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Isoquinoline – Wikipedia,
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TRIAZOLE DERIVATIVE, HETEROCYCLIC COMPOUND, LIGHT-EMITTING ELEMENT, LIGHT-EMITTING DEVICE, ELECTRONIC DEVICE AND LIGHTING DEVICE

A substance that facilitates hole injection and has high triplet excitation energy is provided. A light-emitting element having high efficiency or a long lifetime is provided. A light-emitting element driven with a low voltage is provided. Provided is a light-emitting element including triazolo[4,3-f]phenanthridine derivative (G0) or a triazolo[3,4-a]isoquinoline derivative (G4). Provided are triazolo[4,3-f]phenanthridine(G0) and triazolo[3,4-a]isoquinoline(G4) derivatives, which are novel and can be used for the light-emitting element. [wherein E, Ar, A, and X have the designation cited in claims.]

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Helquats: A facile, modular, scalable route to novel helical dications

The synthesis and properties of helical extended diquat (helquat), and derivatives that bear resemblance to diquat and azoniahelicene, was reported. Triyne with elongated tethers connecting the heterocyclic moiety with the pendant alkyne functionalities undergoing cycloisomerization give helquat featuring two seven-membered rings. The seven helquats reported are accessed uniformly in three steps from commercially available starting materials, entailing a Sonogashira coupling, bisquaternization, cycloisomerization, and [2+2+2] cycloisomerization. The evidence for the reversible electrochemical Weiz-type manifold and regular columnar stacks in crystal structures suggest the potential of helquats as electroactive functional elements.

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Room temperature cross-coupling of highly functionalized organozinc reagents with thiomethylated N-heterocycles by nickel catalysis

“Chemical Equation Presented” A variety of thiomethyl-substituted N-heterocycles such as pyridines, isoquinolines, pyrimidines, pyrazines, pyridazines, quinazolines, triazines, benzothiazoles, or benzoxazoles undergo smooth Ni-catalyzed cross-coupling reactions with functionalized aryl-, heteroaryl-, alkyl-, and benzylic zinc reagents using an inexpensive Ni(acac)2/ DPE-Phos catalytic system at 25C.

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Base has been shown to have a remarkable effect on acceleration of the rate of Suzuki coupling of sterically bulky boronic acid with halopyridines in non-aqueous solvent.

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