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Related Concept Videos

The Two-State Receptor Model01:29

The Two-State Receptor Model

The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with one...
Drug-Receptor Interaction: Agonist01:25

Drug-Receptor Interaction: Agonist

Agonists are drugs that interact with specific receptors in the body to produce a biological response. When an agonist binds to a receptor, it activates or enhances the receptor's function, leading to physiological effects. The interaction between agonist drugs and receptors is crucial for their therapeutic action in various medical treatments.
Agonists can bind to receptors in different ways. Some agonists bind directly to the receptor's active site, mimicking the endogenous ligand's action.
Glucagon-like Receptor Agonists01:24

Glucagon-like Receptor Agonists

Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by the...
Spare Receptors01:30

Spare Receptors

Some receptors remain unoccupied even when an agonist produces a maximal response. Such empty ones are called spare receptors. In presence of spare receptors the maximum effect of an agonist drug is achieved with fewer than 100% of the receptors being occupied. To determine the presence of spare receptors, scientists often compare the concentration of the drug needed to produce 50% of the maximum effect (EC50) with the concentration of the drug needed to occupy 50% of the receptors (Kd). If the...
GPCR Desensitization01:12

GPCR Desensitization

G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of cells.
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Optimizing the Genetic Incorporation of Chemical Probes into GPCRs for Photo-crosslinking Mapping and Bioorthogonal Chemistry in Live Mammalian Cells
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Unique interaction pattern for a functionally biased ghrelin receptor agonist.

Bjørn Sivertsen1, Manja Lang, Thomas M Frimurer

  • 1Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, University of Copenhagen, Blegdamsvej 3b, DK-2200, Copenhagen, Denmark.

The Journal of Biological Chemistry
|March 16, 2011
PubMed
Summary
This summary is machine-generated.

Researchers developed novel peptide-mimetic agonists for the ghrelin receptor, discovering a functionally biased agonist (wFw-Isn-NH(2)) that signals differently from previous compounds. This biased signaling is linked to a unique interaction pattern with the ghrelin receptor.

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Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Molecular Biology

Background:

  • The ghrelin receptor is a key target for metabolic and endocrine disorders.
  • Existing ghrelin receptor agonists are typically unbiased, activating multiple downstream pathways.
  • Development of novel ligands with distinct signaling profiles is crucial for understanding receptor function.

Purpose of the Study:

  • To design and synthesize novel, small, peptide-mimetic agonists for the ghrelin receptor.
  • To investigate the functional activity and signaling bias of newly generated compounds.
  • To elucidate the molecular recognition and binding mode of a novel biased agonist.

Main Methods:

  • Synthesis of conformationally constrained peptide-mimetics based on the D-Trp-Phe-D-Trp (wFw) core.
  • Functional assays to determine agonism potency, efficacy, and signaling pathway activation (Gα(q), ERK1/2, SRE).
  • Molecular modeling and docking experiments to predict ligand-receptor interactions.

Main Results:

  • Novel wFw-based peptide-mimetics achieved nanomolar potency and significant efficacy at the ghrelin receptor.
  • The compound wFw-Isonipecotic acid amide (wFw-Isn-NH(2)) demonstrated functional bias, activating Gα(q)/ERK1/2 but not SRE pathways.
  • Molecular modeling revealed wFw-Isn-NH(2) binds in the classical site but with an opposite orientation, lacking interaction with key TM III residues.

Conclusions:

  • wFw-Isn-NH(2) represents a novel, functionally biased ghrelin receptor agonist.
  • The observed biased signaling is attributed to a unique receptor recognition pattern, distinct from unbiased agonists.
  • This discovery opens new avenues for developing selective ghrelin receptor modulators with tailored therapeutic potential.