Combinatorial synthesis of 3-(Amidoalkyl) and 3-(Aminoalkyl)-2-arylindole derivatives: discovery of potent ligands for a variety of G-protein coupled receptors

Willoughby, Christopher A.; Hutchins, Steven M.; Rosauer, Keith G.; Dhar, Madhumeeta J; Chapman, Kevin T.; Chicchi, Gary G.; Sadowski, S.; Weinberg, David H.; Patel, Smita S.; Malkowitz, Lorraine; Salvo, Jerry Di; Pacholok, Stephen; Cheng, Kang

doi:10.1016/s0960-894x(01)00665-5

Cited by 54 publications

(41 citation statements)

References 15 publications

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“…[88][89][90] The 2-arylindole scaffold illustrated in Figure 4 represents a particularly successful example and was shown at Merck to generate actives for diverse class A GPCRs. [91] In the view of the abovementioned modeling of the ligand-receptor interactions, the privileged structural classes require further analysis to allow a more directed use of such libraries for specific receptor subsets. The development of chemoinformatics methods and procedures enabling the automatic identification and extraction of privileged structures is especially needed in the context of generating knowledge from HTS data.…”

Section: Designing Compound Libraries Targeting Gpcrsmentioning

confidence: 99%

The 7 TM G‐Protein‐Coupled Receptor Target Family

et al. 2006

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Chemical biology approaches have a long history in the exploration of the G-protein-coupled receptor (GPCR) family, which represents the largest and most important group of targets for therapeutics. The analysis of the human genome revealed a significant number of new members with unknown physiological function which are today the focus of many reverse pharmacology drug-discovery programs. As the seven hydrophobic transmembrane segments are a defining common structural feature of these receptors, and as signaling through heterotrimeric G proteins is not demonstrated in all cases, these proteins are also referred to as seven transmembrane (7 TM) or serpentine receptors. This review summarizes important historic milestones of GPCR research, from the beginning, when pharmacology was mainly descriptive, to the age of modern molecular biology, with the cloning of the first receptor and now the availability of the entire human GPCR repertoire at the sequence and protein level. It shows how GPCR-directed drug discovery was initially based on the careful testing of a few specifically made chemical compounds and is today pursued with modern drug-discovery approaches, including combinatorial library design, structural biology, molecular informatics, and advanced screening technologies for the identification of new compounds that activate or inhibit GPCRs specifically. Such compounds, in conjunction with other new technologies, allow us to study the role of receptors in physiology and medicine, and will hopefully result in novel therapies. We also outline how basic research on the signaling and regulatory mechanisms of GPCRs is advancing, leading to the discovery of new GPCR-interacting proteins and thus opening new perspectives for drug development. Practical examples from GPCR expression studies, HTS (high-throughput screening), and the design of monoamine-related GPCR-focused combinatorial libraries illustrate ongoing GPCR chemical biology research. Finally, we outline future progress that may relate today's discoveries to the development of new medicines.

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Section: Designing Compound Libraries Targeting Gpcrsmentioning

confidence: 99%

The 7 TM G‐Protein‐Coupled Receptor Target Family

et al. 2006

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“…Structures of hMC4R small-molecule agonists. Putative arrangement of the N-terminal fragment (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) inside the binding pocket of hMC4R, docked similarly to the peptide agonistα-MSH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). The N-terminal fragment is shown in the licorice representation colored by element,α-MSH is shown by a thin purple line.…”

Section: Supplementary Materialsmentioning

confidence: 99%

“…Consequently research efforts have been focused on the development of potent and MC4R-selective agonists as potential anti-obesity drugs or as treatments for sexual dysfunction (18,19). On the other hand, MC4R antagonists that block the satiety-inducing effect of α-MSH could be helpful for treatment of anorexia or cancer cachexia (20).Recently a number of small-molecule MC4R agonists and antagonists have been synthesized using "privileged structures" formerly employed in other GPCR ligands (21,22). In particular, THIQ and MB243 ( Figure 1) were identified as potent MC4R agonists with >100 fold selectivity over MC1R, MC3R and MC5R (18,19).…”

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confidence: 99%

Interactions of Human Melanocortin 4 Receptor with Nonpeptide and Peptide Agonists^,

et al. 2005

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Specific interactions of human melanocortin-4 receptor (hMC4R) with its non-peptide and peptide agonists were studied using alanine-scanning mutagenesis. The binding affinities and potencies of two synthetic small-molecule agonists (THIQ, MB243) were strongly affected by substitutions in transmembrane α-helices (TM) 2, 3, 6, and 7 (residues Glu 100 Asp 122 , Asp 126 , Phe 261 , His 264 , Leu 265 , and Leu 288 ). In addition, I129A mutation primarily affected binding and potency of THIQ, while F262A, W258A, Y268A mutations impaired interactions with MB243. By contrast, binding affinity and potency of the linear peptide agonist NDP-MSH were substantially reduced only in D126A and H264A mutants. 3D models of receptor-ligand complexes with their agonists were generated by distance geometry using the experimental, homology-based, and other structural constraints, including interhelical H-bonds and two disulfide bridges (Cys 40 -Cys 279 , Cys 271 -Cys 277 ) of hMC4R. In the models, all pharmacophore elements of small-molecule agonists are spatially overlapped with the corresponding key residues (His 6 , D-Phe 7 , Arg 8 and Trp 9 ) of the linear peptide: their charged amine groups interact with acidic residues from TM2 and TM3, similar to His 6 and Arg 6 of NDP-MSH; their substituted piperidines mimic Trp 9 of the peptide and interact with TM5 and TM6; while the D-Phe aromatic rings of all three agonists contact with Leu 133 , Trp 258 , and Phe 261 residues.Melanotropins, which include melanocyte-stimulating hormones (α-, β-, and γ-MSH) and adrenocorticotropic hormone (ACTH), are the products of proteolytic cleavage of the 31-36 kDa precursor, pro-opiomelanocortin (1). α-MSH (Ac-Ser 1 -Tyr 2 -Ser 3 -Met 4 -Glu 5 -His 6 -Phe 7 -Arg 8 -Trp 9 -Gly 10 -Lys 11 -Pro 12 -Val 13 -NH 2 ) shares with all melanotropins the central core tetrapeptide 'His 6 -Phe 7 -Arg 8 -Trp 9 ', which is essential for its biological activity (2). These neuropeptides exert their function through five subtypes of melanocortin receptors (MCRs), which have been cloned and characterized (1,3). MCRs belong to the G protein-coupled receptor (GPCR) superfamily (4) and are positively coupled to cAMP-generation by adenylate cyclase via the stimulatory Gs-proteins. They are involved in regulation of multiple physiological functions, such as pigmentation (MC1R), adrenal cortical steroidogenesis † This work was supported by NIH grants DK054032 (I. Table of receptor type-specific distance constraints for the distance geometry refinement of the model of the active conformation of MC4R. This material is available free of charge via the Internet at http://pubs.acs.org.G NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2008 September 8. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript (MC2R), exocrine secretion (MC5R), energy homeostasis, penile erection (MC3R and MC4R) and many others (1,5,6).The MC4R subtype is regarded as a potential drug target, because it is involved in feeding and sexual ...

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“…141 Fischer indole synthesis on a resinbound aryl ketone using a safety catch linker allowed the use of amine nucleophiles at the final step to release the compounds as amides (Scheme 2.17). Two 64 000 compound libraries were thus prepared, as pools each containing 400 compounds.…”

Section: Lead Discovery: Split and MIX Examplesmentioning

confidence: 99%

High Throughput Chemistry in Drug Discovery

Merritt¹

2011

New Synthetic Technologies in Medicinal Chemistry

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This chapter outlines the evolution of high throughput chemistry from its origins in the genome revolution of the early 1990's to its current practice as an integral tool in drug discovery, via the concept of the large “universal library” to the practice of small targeted arrays for structure–activity relationship generation. The technologies developed as part of this evolution are also outlined including early ACT peptide synthesisers and other automated and non-automated devices for both solid-supported and solution-based approaches. Finally, the chapter outlines several case studies of the application of high throughput synthesis to drug discovery.

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Combinatorial synthesis of 3-(Amidoalkyl) and 3-(Aminoalkyl)-2-arylindole derivatives: discovery of potent ligands for a variety of G-protein coupled receptors

Cited by 54 publications

References 15 publications

The 7 TM G‐Protein‐Coupled Receptor Target Family

The 7 TM G‐Protein‐Coupled Receptor Target Family

Interactions of Human Melanocortin 4 Receptor with Nonpeptide and Peptide Agonists^,

High Throughput Chemistry in Drug Discovery

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Combinatorial synthesis of 3-(Amidoalkyl) and 3-(Aminoalkyl)-2-arylindole derivatives: discovery of potent ligands for a variety of G-protein coupled receptors

Cited by 54 publications

References 15 publications

The 7 TM G‐Protein‐Coupled Receptor Target Family

The 7 TM G‐Protein‐Coupled Receptor Target Family

Interactions of Human Melanocortin 4 Receptor with Nonpeptide and Peptide Agonists,

High Throughput Chemistry in Drug Discovery

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Product

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Interactions of Human Melanocortin 4 Receptor with Nonpeptide and Peptide Agonists^,