Hexarelin: Molecular Structure

Molecular Structure#

Hexarelin is a synthetic hexapeptide growth hormone secretagogue (GHS) with the amino acid sequence His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2. Its molecular weight is approximately 887.0 Da, with the molecular formula C47H58N12O6 and CAS registry number 140703-51-1. The peptide consists of six amino acid residues, two of which are non-natural D-configured amino acids, and the C-terminus is amidated. These structural modifications were deliberately introduced to enhance receptor binding affinity and confer resistance to enzymatic degradation, distinguishing hexarelin from earlier, less optimized growth hormone releasing peptides.

Amino Acid Sequence and Residue Analysis#

The primary structure of hexarelin is a linear hexapeptide: His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2. Each residue contributes specific functional and structural properties.

• Position 1 -- Histidine (His): The N-terminal histidine provides an imidazole side chain capable of hydrogen bonding and pH-dependent protonation. Histidine at this position is shared across several GHRP family members and contributes to receptor interaction geometry.
• Position 2 -- D-2-Methyltryptophan (D-2-methyl-Trp): This is a non-natural residue with two key modifications: inversion of stereochemistry to the D-configuration and addition of a methyl group at the 2-position of the indole ring. The D-configuration confers resistance to proteolytic cleavage by L-amino acid-specific endopeptidases, while the 2-methyl substitution on the indole increases hydrophobic contact area with the GHS-R1a receptor binding pocket, contributing to hexarelin's enhanced binding potency relative to earlier GHRPs.
• Position 3 -- Alanine (Ala): A small, hydrophobic residue that serves as a conformational spacer, maintaining appropriate backbone geometry between the aromatic residues at positions 2 and 4.
• Position 4 -- Tryptophan (Trp): The natural L-tryptophan at this position provides a second indole ring system critical for hydrophobic interactions within the GHS-R1a receptor binding cleft. The presence of two tryptophan-derived residues (positions 2 and 4) is a defining feature of hexarelin's pharmacophore.
• Position 5 -- D-Phenylalanine (D-Phe): Another D-configured residue, D-phenylalanine contributes an aromatic side chain while further enhancing proteolytic stability. The D-Phe at position 5 is a conserved feature among potent GHRPs and participates in hydrophobic stacking interactions with receptor residues.
• Position 6 -- Lysine-NH2 (Lys-NH2): The C-terminal lysine provides a cationic epsilon-amino group for electrostatic interactions with the receptor. The C-terminal amidation eliminates the negative charge of the free carboxylate, improving membrane permeability, receptor binding, and resistance to carboxypeptidase degradation.

D-Amino Acid Modifications and Protease Resistance#

The incorporation of D-amino acids at positions 2 and 5 is a deliberate design strategy to improve metabolic stability. Natural L-peptides are rapidly degraded by endogenous proteases, particularly aminopeptidases and endopeptidases that recognize L-configured substrates. D-amino acids at these positions create non-natural peptide bonds that are poorly recognized by these enzymes, extending the effective plasma half-life of hexarelin to approximately 60 to 70 minutes, considerably longer than unmodified hexapeptides of comparable size.

The 2-methyl substitution on the D-tryptophan at position 2 provides additional steric shielding against enzymatic attack while simultaneously enhancing hydrophobic interaction with the GHS-R1a binding site. This dual benefit of increased stability and potency exemplifies modern peptide medicinal chemistry approaches.

The C-terminal amidation further contributes to stability by blocking carboxypeptidase-mediated degradation from the C-terminus. Together, these three modifications -- two D-amino acids and C-terminal amidation -- transform the hexapeptide from a rapidly degraded peptide into a compound with sufficient metabolic stability for pharmacological activity after parenteral administration.

GHS-R1a Receptor Binding#

Hexarelin's primary pharmacological target is the growth hormone secretagogue receptor type 1a (GHS-R1a), a seven-transmembrane G protein-coupled receptor (GPCR) expressed predominantly in the hypothalamus and anterior pituitary gland. GHS-R1a was subsequently identified as the receptor for the endogenous hormone ghrelin.

The binding interaction involves extensive hydrophobic contacts between hexarelin's aromatic residues (D-2-methyl-Trp, Trp, D-Phe) and hydrophobic residues lining the transmembrane binding pocket of GHS-R1a. The cationic N-terminal histidine and C-terminal lysine form electrostatic and hydrogen-bonding interactions with polar residues at the receptor surface. Structure-activity relationship studies within the GHRP family have demonstrated that the aromatic triad formed by positions 2, 4, and 5 is essential for high-affinity binding, and hexarelin's specific combination of modifications optimizes this interaction.

Among synthetic GHS peptides, hexarelin is generally considered to exhibit the highest binding affinity and functional potency at GHS-R1a, producing the most robust acute growth hormone release per dose. This potency advantage is attributed to the 2-methyl group on the D-tryptophan residue, which enhances hydrophobic complementarity with the receptor binding pocket beyond what is achieved by unsubstituted D-tryptophan found in GHRP-6 or GHRP-2.

CD36 Scavenger Receptor Interaction#

A distinctive pharmacological feature of hexarelin among GHS peptides is its binding to the CD36 scavenger receptor, a class B scavenger receptor with broad tissue expression on cardiomyocytes, macrophages, endothelial cells, adipocytes, and platelets. This interaction is independent of GHS-R1a binding and mediates hexarelin's cardioprotective effects.

The structural determinants of hexarelin's CD36 binding have not been fully characterized at atomic resolution, but studies using GHS-R1a knockout animals and CD36-deficient models have confirmed that the cardioprotective effects are CD36-dependent and GHS-R1a-independent. This dual receptor binding profile is not shared by all GHS peptides -- GHRP-6 and ipamorelin, for example, show negligible CD36 interaction -- suggesting that specific features of hexarelin's structure, potentially the 2-methyl-tryptophan modification or the overall hydrophobic surface topology, enable this secondary receptor engagement.

Through CD36, hexarelin activates peroxisome proliferator-activated receptor gamma (PPAR-gamma) signaling, promotes anti-inflammatory gene expression, and modulates lipid metabolism in cardiac tissue.

Physicochemical Properties and Stability#

Hexarelin is typically supplied as a lyophilized white powder, often as the acetate salt form (hexarelin acetate). Key physicochemical properties include the following.

• Molecular weight: 887.0 Da (free base)
• Molecular formula: C47H58N12O6
• Solubility: Freely soluble in water and dilute aqueous buffers at physiological pH. Soluble in dimethyl sulfoxide (DMSO) for concentrated stock preparation.
• Stability in solution: Reconstituted solutions are stable when stored at 2 to 8 degrees Celsius and protected from light, with recommended use within two to four weeks of reconstitution. The D-amino acid modifications and C-terminal amidation confer substantially greater stability than would be expected for an unmodified hexapeptide.
• Lyophilized stability: The lyophilized powder is stable for extended periods when stored at minus 20 degrees Celsius, protected from moisture and light.
• pH sensitivity: Hexarelin maintains structural integrity across a pH range of approximately 4 to 8, with optimal stability near neutral pH. Strongly acidic or alkaline conditions can promote hydrolysis of peptide bonds.

Pharmacokinetic Considerations#

Following subcutaneous or intravenous administration, hexarelin is absorbed rapidly into the systemic circulation. The estimated plasma half-life of approximately 60 to 70 minutes reflects the protective effects of its D-amino acid modifications and C-terminal amidation against proteolytic degradation. Peak growth hormone release typically occurs within 15 to 30 minutes of intravenous administration, indicating rapid receptor engagement.

Metabolism proceeds through proteolytic cleavage of accessible peptide bonds by non-specific plasma and tissue peptidases, generating smaller peptide fragments and free amino acids. The D-amino acid-containing bonds are more resistant to this degradation, which accounts for the extended half-life relative to unmodified peptides. Elimination of the parent compound and metabolites occurs primarily through renal clearance.

The relatively short half-life, while extended compared to unmodified hexapeptides, remains a pharmacological consideration for sustained GH stimulation and has led to the investigation of multiple daily dosing protocols in research settings.

Related Reading#

• Hexarelin overview and research guide
• Peptides similar to Hexarelin
• Hexarelin research evidence