Melanin-Concentrating Hormone Receptor 1 Antagonists. Synthesis and Structure–Activity Relationships of Novel 3-(Aminomethyl)quinolines

Abstract

It was found that 3-(aminomethyl)quinoline derivatives showed high binding affinities for melanin-concentrating hormone receptor 1 (MCHR1) with reduced affinity for serotonin receptor 2c (5-HT2c) when the dihydronaphthalene nucleus of compound 1 (human MCHR1, IC(50) = 1.9 nM; human 5-HT2c receptor, IC(50) = 0.53 nM) was replaced by other bicyclic core scaffolds. Among the synthesized compounds, 8-methylquinoline derivative 5v especially showed high binding affinity (IC(50) = 0.54 nM), potent in vitro antagonistic activity (IC(50) = 2.8 nM) for MCHR1, and negligible affinity for 5-HT2c receptor (IC(50) > 1000 nM). Oral administration of 5v significantly and dose-dependently suppressed nocturnal food intake in diet-induced obese rats and did not affect food intake in MCHR1-deficient mice. These results and rat pharmacokinetic study findings suggested that compound 5v is a highly potent, orally bioavailable, and centrally acting nonpeptide MCHR1 antagonist.

Inhibition of melanogenesis by jineol from Scolopendra subspinipes mutilans via MAP-Kinase mediated MITF downregulation and the proteasomal degradation of tyrosinase

“…Previous studies revealed that the 5-HT2c receptor of 8-methylquinoline acts as a potent MCHR1 antagonist35. In addition, 4-substituted amino quinoline derivatives, such as, chloroquine and quinine, have been reported to inhibit melanogenesis and to involve disturbance of tyrosinase family member trafficking36.…”

Nickel‐Promoted Highly Regioselective Carboxylation of Aryl Ynol Ether and Its Application to the Synthesis of Chiral β‐Aryloxypropionic Acid Derivatives

“…Scheme3.Structuralelucidation of 8a. fects of the alkyne moiety were also investigated (entries [6][7][8][9][10][11][12]. It was found that various functional groups including oxygen functionalities were tolerated, and the corresponding b-aryloxypropionic acid derivatives 8g-8m wereo btained in good to excellent yields.…”

“…[4] They are also recognized as valuables ubstrates for the synthesiso fb iologically active b-aminoalcohols [5] and chroman-4-one derivatives. [6] Therefore, av ariety of methodologies for the synthesis of b-aryloxypropionic acid derivatives as an enantioenriched form have been reported. [7] One straightforward and promising methodf or the synthesis of enantioenriched b-aryloxypropionic acid derivatives is the asymmetrichydrogenation of the b-aryloxyacrylate derivatives, and iridium- [8a,b] and rhodium-catalyzed [8c] hydrogenation reactions have recently been demonstrated.…”

Cp*Rh(III)‐Catalyzed Directed C−H Methylation and Arylation of Quinoline N‐Oxides at the C‐8 Position

“…Quinoline is an important structural motif in drug discovery and materials science . Notably, 8‐methylquinoline derivatives are found in many drugs and biologically active molecules (Scheme ) . Accordingly, the development of efficient methods to produce substituted quinoline is important.…”

“…[5] Notably, 8-methylquinoline derivatives are found in many drugs and biologically active molecules (Scheme 1). [6][7][8] Accordingly, the development of efficient methods to produce substituted quinoline is important. Over the past few decades, transition-metal-catalyzed CÀH functionalization has emerged as a powerful strategy to synthesize complex molecules.…”