2-Piperazinecarboxamides as potent and selective melanocortin subtype-4 receptor agonists

Palucki, Brenda L.; Park, Min K.; Nargund, Ravi P.; Tang, Rui; MacNeil, Tanya; Weinberg, David H.; Vongs, Aurawan; Rosenblum, Charles; Doss, George A.; Miller, Randall R.; Stearns, Ralph A.; Peng, Qianping; Tamvakopoulos, Constantin; Ploeg, Lex H.T. Van der; Patchett, Arthur A.

doi:10.1016/j.bmcl.2005.02.068

Cited by 27 publications

(33 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This allowed the development of putative 3D models of complexes of hMC4R with either THIQ or MB243, based on current data, SAR of smallmolecule agonists (18,19), and our previous modeling studies of inactive (antagonist-bound) and active (agonist-bound) states of different GPCRs (31,33). Subsequently, the models of hMC4R with two linear peptide agonists, NDP-MSH andα-MSH, were calculated by distance (16,47,(51)(52)(53).…”

Section: Discussionmentioning

confidence: 99%

“…Pharmacological studies indicate that activation of the MC4R in rodents modulates erectile function (9). 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).…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…In particular, THIQ and MB243 ( Figure 1) were identified as potent MC4R agonists with >100 fold selectivity over MC1R, MC3R and MC5R (18,19).…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…Our data indicate that the most important interaction likely involve charged residues (Glu 100 , Asp 122 , Asp 126 , and His 264 ), residues from TM6 (Phe 261 Leu 265 ,) and from TM7 (Leu 288 ), as their mutations decrease IC 50 and EC 50 of both agonists more than 10 fold. These residues are relatively conserved for MCRs 1, 3, 4, and 5 and therefore are not likely to be involved in the specific interactions with MC4R that provide >100 fold selectivity of these agonists over MC1R, MC3R, and MC5R (18,19). To reveal the ligandreceptor interactions responsible for the selectivity of these agonists would require additional mutations in other sites of the binding pocket, particularly, in the positions of variable residues The binding affinities and potencies of small agonists are more sensitive to point mutations than those of peptide agonists: receptor activation by the linear peptide agonist, NDP-MSH, is strongly affected only by D126A and H264A mutations (potency decreased more than 80 fold), and, to a lesser extent, by the E100A mutation.…”

Section: Interactions Of Agonists With Hmc4r Residuesmentioning

confidence: 99%

“…The proposed peptide-receptor complexes were consistent with the notion that the core residues of flexible peptides reproduced the receptorbound structure of the more conformationally rigid small molecule agonists. The peptide flexibility was also restrained during calculation by packing interactions and H-bonds with the receptor, and by several intramolecular cross-linking constraints taken from related bioactive cyclic peptides.The most important pharmacophore element of all melanocortin agonists is an aromatic ring of the central D-Phe residue (18,19,49,54). It is inserted at the bottom of the binding cavity in close proximity to the conserved Trp 258 residue that triggers activation of GPCRs (31,55).…”

mentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2005

Self Cite

View full text Add to dashboard Cite

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 ...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…In particular, THIQ and MB243 ( Figure 1) were identified as potent MC4R agonists with >100 fold selectivity over MC1R, MC3R and MC5R (18,19).…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Section: Interactions Of Agonists With Hmc4r Residuesmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2005

Self Cite

View full text Add to dashboard Cite

show abstract

Case Studies on Eliminating/Reducing Reactive Metabolite Formation in Drug Discovery

Kalgutkar

Dalvie

Obach

et al. 2012

Reactive Drug Metabolites

View full text Add to dashboard Cite

Selectively N‐Protected Enantiopure 2,5‐Disubstituted Piperazines: Avoiding the Pitfalls in Solid‐Phase Fukuyama–Mitsunobu Cyclizations

Ottesen

Olsen

Witt

et al. 2009

Chemistry A European J

View full text Add to dashboard Cite

An efficient solid-phase route to ring-substituted piperazines from O-linked resin-bound (S)-aziridine-2-methanol is described. Regioselective microwave-assisted aminolysis followed by intramolecular Fukuyama-Mitsunobu cyclization constitute the key features of the protocol. Simple piperazines and diazepanes were readily obtained without preceding N-protection of the acyclic intermediate, whereas attempts to extend this protocol to chiral 2,5-disubstituted piperazines failed. Modifications encompassing N-carbamoylation prior to ring-closure were therefore investigated. However, standard carbamoylating agents, for example, Fmoc-Cl and Alloc-Cl tended to give bis-protected by-products. Thus, novel microwave-assisted solid-phase N-protection procedures were developed for efficient introduction of Fmoc, Boc and Alloc groups. The subsequent cyclization proceeded in moderate to excellent yields depending on the bulk of the side chain and type of N-protecting group. This protocol readily provided novel cis- and trans-2,5-disubstituted piperazines displaying a variety of N-protecting group patterns after further on-resin manipulations. Also, unexpected by-products obtained during these optimization studies were identified and characterized. This includes nosylated ureas arising from an alternative cyclization pathway. Finally, post-cleavage oxidation gave access to the Fmoc/Boc-protected alpha-amino acid as well as the corresponding aldehyde. The chiral piperazines described in this work will enable construction of combinatorial libraries with a higher chemical diversity compared to those containing simple N,N'-difunctionalized piperazines, often present in drug-like compounds.

show abstract

2-Piperazinecarboxamides as potent and selective melanocortin subtype-4 receptor agonists

Cited by 27 publications

References 14 publications

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

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

Case Studies on Eliminating/Reducing Reactive Metabolite Formation in Drug Discovery

Selectively N‐Protected Enantiopure 2,5‐Disubstituted Piperazines: Avoiding the Pitfalls in Solid‐Phase Fukuyama–Mitsunobu Cyclizations

Contact Info

Product

Resources

About

2-Piperazinecarboxamides as potent and selective melanocortin subtype-4 receptor agonists

Cited by 27 publications

References 14 publications

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

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

Case Studies on Eliminating/Reducing Reactive Metabolite Formation in Drug Discovery

Selectively N‐Protected Enantiopure 2,5‐Disubstituted Piperazines: Avoiding the Pitfalls in Solid‐Phase Fukuyama–Mitsunobu Cyclizations

Contact Info

Product

Resources

About

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

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