Heterocyclic aminopyrrolidine derivatives as melatoninergic agents

Sun, Li‐Qiang; Chen, Jie; Mattson, Ronald J.; Epperson, James R.; Deskus, Jeffrey A.; Li, Wen-Sen; Takaki, Katherine S.; Hodges, Donald B.; Iben, Lawrence G.; Mahle, Cathy D.; Ortiz, Astrid; Molstad, David H. H.; Ryan, Elaine; Yeleswaram, Krishnaswamy; Xu, Cen; Luo, Guanglin

doi:10.1016/j.bmcl.2003.09.030

Cited by 14 publications

(1 citation statement)

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“…The benzoxazole scaffold is also found in MT 1 selective agonists, which will be described later. A constrained side chain and a phenyl ring, fused with a five-membered ring mimicking the methoxy group, are present in the pyrrolidine derivative 20, a non-selective agonist with binding affinity similar to MLT (in its (R) configuration) and moderate stereoselectivity [130]. An open-chain analog approach, starting from tetralin and tricyclic scaffolds [131] and a subsequent replacement of a carbon with a nitrogen atom led to the class of anilinoethylamides [132], that include the non-selective agonist 21 and the MT 2 selective partial agonist UCM765 (Ki = 4.17 nM and 0.067 nM at MT 1 and MT 2 receptor, respectively).…”

Section: New Classes Of Agonistsmentioning

confidence: 99%

Melatonin Receptor Agonists: SAR and Applications to the Treatment of Sleep-Wake Disorders

Rivara¹,

Mor²,

Bedini³

et al. 2008

CTMC

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Melatonin (N-acetyl-5-methoxytryptamine) is synthesized and released by the pineal gland following a circadian rhythm characterized by high levels during the night. It shows several pharmacological effects on diverse cellular and animal models, mainly related to either its antioxidant activity or to its ability to activate specific receptors (MTr). Melatonin is widely used as a self-administered food additive, but its therapeutic potential needs more investigation and is hampered by its poor pharmacokinetics. This review will focus on the medicinal chemistry of agonist ligands of the two human GPCRs MT(1) and MT(2) melatonin receptors. The recent introduction of ramelteon, a non-selective MT(1)/MT(2) agonist for the treatment of insomnia, and the advancement to clinical trials of other MTr agonists have renewed interest for different classes of compounds endowed with this activity. Several chemical classes of MTr agonists are described in the literature, generally characterized by an indole, or an indole bioisostere, carrying an amide side chain and a methoxy group, or substituents with similar stereoelectronic features. Abundant information is available for non-selective MT(1)/MT(2) ligands, and several molecular models, both ligand- and receptor-based, have been proposed to rationalize their structure activity relationships. Fewer classes of selective agonists have been reported in the literature, and they could help clarifying the physiological role of the two receptor subtypes. A brief discussion on the therapeutic potential of this class of compounds is based on the clinical data available for the agonists ramelteon, agomelatine, beta-methyl-6-chloromelatonin (TIK-301) and VEC-162.

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