Design and Pharmacology of N-[(3R)-1,2,3,4-Tetrahydroisoquinolinium- 3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)- 2-[4-cyclohexyl-4-(1H-1,2,4-triazol- 1-ylmethyl)piperidin-1-yl]-2-oxoethylamine (1), a Potent, Selective, Melanocortin Subtype-4 Receptor Agonist

Sebhat, Iyassu K.; Martin, William J.; Ye, Zhixiong; Barakat, Khaled; Mosley, Ralph T.; Johnston, David B.; Bakshi, Raman K.; Palucki, Brenda L.; Weinberg, David H.; MacNeil, Tanya; Kalyani, Rubana N.; Tang, Rui; Stearns, Ralph A.; Miller, Randy R.; Tamvakopoulos, Constantin; Strack, Alison M.; McGowan, Erin; Cashen, Doreen E.; Drisko, Jennifer E.; Hom, Gary J.; Howard, Andrew D.; MacIntyre, D. Euan; Ploeg, Lex H.T. Van der; Patchett, and Arthur A.; Nargund, Ravi P.

doi:10.1021/jm025539h

Cited by 178 publications

(132 citation statements)

References 27 publications

(63 reference statements)

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“…Our initial design was inspired by the common structural features between MC-4 receptor agonist, discovered by Merck, and fentanyl, a potent l opioid receptor agonist (Figure 1). 20 Both structures have a piperidine scaffold appended with aromatic moieties. Ligand 6 was designed by the replacement of the 4-cyclohexyl-4- We systematically modified ligand 6 and performed structure-activity relationship (SAR) studies at both recep-FIGURE 1 Ligands for structure-activity relationships study.…”

Section: Resultsmentioning

confidence: 99%

Opioid and melanocortin receptors: Do they have overlapping pharmacophores?

et al. 2008

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We have identified compound 1 as a novel ligand for opioid and melanocortin (MC) receptors, which is derived from the overlapping of a well known structure for the δ opioid receptor, 2,6‐dimethyltyrosine (Dmt)‐1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid (Tic), and a small molecule for the MC receptor, Tic‐DPhe(p‐Cl)‐piperidin‐4‐yl‐N‐phenyl‐propionamide. Ligand 1 showed that there is an overlapping pharmacophore between opioid and MC receptors through the Tic residue. The ligand displayed high biological activities at the δ opioid receptor (Ki = 0.38 nM in binding assay, EC50 = 0.48 nM in GTP‐γ‐S binding assay, IC50 = 74 nM in MVD) as an agonist instead of an antagonist and showed selective binding affinity (IC50 = 2.3 μM) at the MC‐3 receptor rather than at the MC‐5 receptor. A study of the structure‐activity relationships demonstrated that the residues in positions 2, 3, and the C‐terminus act as a pharmacophore for the MC receptors, and the residues in positions 1 and 2 act as a pharmacophore for the opioid receptors. Thus, this structural construct can be used to prepare chimeric structures with adjacent or overlapping pharmacophores for opioid and MC receptors. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 433–438, 2008.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

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Section: Resultsmentioning

confidence: 99%

Opioid and melanocortin receptors: Do they have overlapping pharmacophores?

et al. 2008

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“…THIQ, which is significantly smaller (Fw=589.169), actually has a lower affinity than peptide ligands and even the 39-amino acid peptide ACTH (Fw=4541.11) is capable of migrating through the yeast cell wall and activating the MC4R. It is reported that THIQ has approximately the same affinity for MC4R as αMSH [24,37]. The lower activity in yeasts may be explained by instability of THIQ in yeast culture where the activation process takes a significantly longer time when compared to the classical cAMP experiments.…”

Section: Discussionmentioning

confidence: 99%

Expression of human melanocortin 4 receptor in Saccharomyces cerevisiae

et al. 2011

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The melanocortin 4 receptor (MC4R) is involved in the regulation of energy homeostasis and is known as one of the major hypothalamic regulators of food intake. Several studies have shown that replacement of aspartic acid at position 126 of the MC4R abolishes the ligand binding. We used the modified yeast Saccharomyces cerevisiae strain MMY28 to functionally express the MC4R and characterise the importance of this amino acid for ligand based activation of the receptor. The efficiency of the functional expression system was estimated by activation with αMSH, ACTH and THIQ and compared with cAMP response in mammalian cells. We generated the library of MC4R mutants randomised at the amino acid position 126. Recombinant MC4R clones were screened for the αMSH induced activity in yeast. From 9 different amino acids obtained only the natural aspartic acid displayed the ligand dependent activity of MC4R. The MC4R variants with glutamic acid and leucine at position 126, however, displayed higher background activity than other amino acid substitutions. The results suggest that the yeast expression system is suitable for screening of the MC4R receptor ligands and that the substitution of aspartic acid at position 126 of MC4R by different amino acids functionally inactivates the receptor.

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“…The amino-acid sequence of the MC4 receptor shares considerable homology with that of other GPCRs for which drugs had already been identified, such as the ghrelin receptor, which binds growth-hormone secretagogue compounds (Bondensgaard et al, 2004). A directed screen of a library containing growth-hormone secretagogue compounds yielded a moderate potency (110 nM) MC4 receptor hit (Sebhat et al, 2002). Compounds elaborated from this initial lead are similar to the bioactive structure of the endogenous peptide agonist a-melanocyte-stimulating hormone and synthetic peptide analogues (Sebhat et al, 2002;Sun et al, 2004).…”

Section: Ligand Structure: Drug Development For Peptide Gpcrsmentioning

confidence: 99%

“…A directed screen of a library containing growth-hormone secretagogue compounds yielded a moderate potency (110 nM) MC4 receptor hit (Sebhat et al, 2002). Compounds elaborated from this initial lead are similar to the bioactive structure of the endogenous peptide agonist a-melanocyte-stimulating hormone and synthetic peptide analogues (Sebhat et al, 2002;Sun et al, 2004). This information was used to guide further medicinal chemistry efforts to optimize small molecule potency for the MC4 receptor.…”

Section: Ligand Structure: Drug Development For Peptide Gpcrsmentioning

confidence: 99%

Drugability of Extracellular Targets: Discovery of Small Molecule Drugs Targeting Allosteric, Functional, and Subunit-Selective Sites on GPCRs and Ion Channels

Grigoriadis

Hoare

Lechner

et al. 2008

Neuropsychopharmacol

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Beginning with the discovery of the structure of deoxyribose nucleic acid in 1953, by James Watson and Francis Crick, the sequencing of the entire human genome some 50 years later, has begun to quantify the classes and types of proteins that may have relevance to human disease with the promise of rapidly identifying compounds that can modulate these proteins so as to have a beneficial and therapeutic outcome. This so called 'drugable space' involves a variety of membrane-bound proteins including the superfamily of G-protein-coupled receptors (GPCRs), ion channels, and transporters among others. The recent number of novel therapeutics targeting membrane-bound extracellular proteins that have reached the market in the past 20 years however pales in magnitude when compared, during the same timeframe, to the advancements made in the technologies available to aid in the discovery of these novel therapeutics. This review will consider select examples of extracellular drugable targets and focus on the GPCRs and ion channels highlighting the corticotropin releasing factor (CRF) type 1 and g-aminobutyric acid receptors, and the Ca V 2.2 voltage-gated ion channel. These examples will elaborate current technological advancements in drug discovery and provide a prospective framework for future drug development.

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Design and Pharmacology of N-[(3R)-1,2,3,4-Tetrahydroisoquinolinium- 3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)- 2-[4-cyclohexyl-4-(1H-1,2,4-triazol- 1-ylmethyl)piperidin-1-yl]-2-oxoethylamine (1), a Potent, Selective, Melanocortin Subtype-4 Receptor Agonist

Cited by 178 publications

References 27 publications

Opioid and melanocortin receptors: Do they have overlapping pharmacophores?

Opioid and melanocortin receptors: Do they have overlapping pharmacophores?

Expression of human melanocortin 4 receptor in Saccharomyces cerevisiae

Drugability of Extracellular Targets: Discovery of Small Molecule Drugs Targeting Allosteric, Functional, and Subunit-Selective Sites on GPCRs and Ion Channels

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