Identification of Novel 1-O-Substituted Aporphine Analogues as Potent 5-HT_2C Receptor Agonists

Abstract

The 5-HT2C receptor has emerged as a promising target in the treatment of a variety of central nervous system disorders. We have first identified aporphines as a new class of 5-HT2C receptor agonists. Structure–activity relationship results indicate that the aporphine core may be required for 5-HT2C receptor activity, and substitutions at its C1 position are important for 5-HT2C receptor activity. Our efforts to optimize our hit 15781 lead to the identification of the highly potent and selective 5-HT2C agonist 18b (MQ02-439) with an EC50 value of 104 nM and weak antagonism at the 5-HT2A and 5-HT2B receptors. The findings may serve as good starting points for the development of more potent and selective 5-HT2C agonists as valuable pharmacological tools or potential drug candidates.

Construction of Indoline-Fused Tetrahydroisoquinolines through a Domino Coupling Reaction Catalyzed by CuCoFe Layered Double Hydroxide

“…N-Containing polycyclic compounds make up an important class for bioactive substances, natural products, and medicine . Construction of various polycyclic compounds through domino or cascade reactions is always an effective method, featuring a high efficiency, a simple process, and easy handling.…”

Identification of Spiro[chromene-2,4′-piperidine]s as Potent, Selective, and Gq-Biased 5-HT2C Receptor Partial Agonists

“…18,23 To develop high subtype and functional selective 5-HT 2C R agonists, our team in 2020 unexpectedly identified a naturally occurring aporphine, (R)asimilobine (1857), as the first G protein-biased and highly selective 5-HT 2C R agonist (EC 50 = 308 nM, E max = 86.1%) through an affinity mass spectrometry approach for screening herbal extracts. 31 Importantly, 1857 did not exhibit any agonistic effect on 5-HT 2A R or 5-HT 2B R. 31 Our early medicinal chemistry work on modifying the substituents of the A ring led to MQ-439 (1) with a 3-fold increase in 5-HT 2C R activation (EC 50 = 103 nM, E max = 96%) with Gprotein exclusive bias and high selectivity against 5-HT 2A R and 5-HT 2B R. 21,32 Unfortunately, compound 1 exhibits a significant hERG inhibition of 92.73% at a concentration of 10 μM. This suggests that it is likely to induce fatal arrhythmia.…”

Synthesis of Aporphine Analogues via Palladium-Catalyzed Intramolecular Aryl–Aryl Dehydrogenative Coupling

“…A representative example is ( R )-(−)-apomorphine hydrochloride, a potent DA-receptor agonist, which has currently been employed in the treatment of Parkinson’s disease and related neurologic diseases . The latest studies on the structure–activity relationship have indicated that the substitutions at the C1 position of the aporphine core might be positive for 5-HT 2C receptor activity, a promising target in the treatment of a variety of central nervous system disorders . Thus, the development of efficient synthetic methods for various C1-substituted aporphines is important and urgent.…”