Semaglutide – GLP-1 Receptor Agonist

Chemical Identity

Chemical Name: Semaglutide Acetate
Molecular Formula: C₁₈₇H₂₉₁N₄₅O₅₉
Molecular Weight: ~4113.6 Da
CAS Number: 910463-68-2
Sequence (Linear): H-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(γGlu-2xOEG-C18 diacid)-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-NH₂
Modifications: Aib at position 8, Lys acylated with C18 fatty diacid via glutamic acid and OEG linker
Structure Type: GLP-1(7-37) analog with extended half-life via albumin binding

Pharmacological Classification

Semaglutide is a potent, long-acting agonist of the glucagon-like peptide-1 receptor (GLP-1R), designed for metabolic regulation including glycemic control and appetite suppression.

Mechanism of Action

• GLP-1R Activation: Stimulates glucose-dependent insulin secretion, inhibits glucagon release, delays gastric emptying, and reduces appetite via central pathways.
• Signaling: Acts via G_s-coupled activation of adenylate cyclase → increased intracellular cAMP → PKA activation and insulin gene transcription.

β-Arrestin Recruitment

Semaglutide functions as a biased GLP-1R agonist:

• GLP-1R: Compared to native GLP-1, semaglutide exhibits reduced β-arrestin recruitment, favoring sustained cAMP signaling over receptor internalization and desensitization.
• This profile may enhance pharmacodynamic durability and mitigate tachyphylaxis during prolonged exposure.

Comparative β-Arrestin Profile

Receptor	Native Ligand	β-Arrestin Recruitment	Semaglutide Activity
GLP-1R	GLP-1	High	Reduced (biased toward cAMP)

References: Jones B et al., Cell 2018;175(3):654–665. Willard FS et al., Cell Reports 2020;33(6):108293.

Molecular Engineering

Substitution of Aib (α-aminoisobutyric acid) at position 8 and acylation at Lys26 with a fatty diacid chain extend plasma half-life and protect from enzymatic degradation by DPP-IV.

Pharmacokinetics (Non-Dosing)

• Elimination: Primarily renal clearance of peptide fragments following proteolysis
• Plasma Protein Binding: >99% (albumin)
• Half-Life: ~160 hours (6–7 days)

Biological Effects

Reduces fasting plasma glucose, enhances β-cell responsiveness, and suppresses appetite by acting on hypothalamic POMC/CART neurons and brainstem GLP-1R sites.

Preclinical Evidence

In rodent and non-human primate models, semaglutide reduced body weight, visceral fat, and HbA1c more effectively than native GLP-1 or liraglutide. Demonstrates dose-proportional exposure and strong metabolic improvements across species.

Stability and Storage

• Form: Lyophilized powder
• Solubility: Water, acidic buffer (pH 4–6), DMSO (analytical)
• Storage: –20°C, light and moisture protected
• Reconstitution pH: 4.5–5.5 preferred

Comparative Mechanistic Summary

Parameter	GLP-1 (native)	Semaglutide
Receptor Affinity	High	High
β-arrestin Recruitment	High	Reduced
Receptor Internalization	Rapid	Slower
Half-life	~2 min	~6–7 days
Albumin Binding	No	Yes

References

1. Jones B, et al. Cell. 2018;175(3):654–665.e16.
2. Willard FS, et al. Cell Reports. 2020;33(6):108293.
3. Kapitza C, et al. Diabetes Obes Metab. 2015;17(2):200–206.
4. Knudsen LB, Lau J. Front Endocrinol. 2019;10:155.
5. Marre M, et al. Diabetes Care. 2017;40(7):821–828.