MK-677 is a non-peptide agonist at the growth hormone secretagogue receptor type 1a, the receptor for ghrelin. It is built on a spiro-indoline scaffold with an O-benzyl serine chain and a methanesulfonamide group, and it was developed as an orally available small molecule alternative to the peptide secretagogues. In cell work it is used as a reference full agonist at GHS-R1a, and its non-peptide chemistry makes it stable in conditions where peptide agonists are degraded.
Key facts
| Type | Non-peptide small molecule, spiro-indoline scaffold |
| Molecular formula | C27H36N4O5S (free base) |
| Molecular weight | 528.7 g/mol (free base) |
| Salt form | Methanesulfonate, C28H40N4O8S2, 624.8 g/mol |
| CAS number | 159752-10-0 (mesylate salt) |
| Receptor target | Growth hormone secretagogue receptor 1a, GHS-R1a |
| Synonyms | Ibutamoren, ibutamoren mesylate, L-163,191 |
| Supplied form | Crystalline solid or capsule, depending on supplier |
Structure and chemistry
The core is a spiro[indoline-3,4′-piperidine] system, a rigid bicyclic arrangement in which the piperidine ring is joined to the indoline at a single shared carbon. That spiro junction fixes the relative orientation of the two ring systems and removes the conformational freedom a simple linked pair would have, which is what allows a small molecule to present the same pharmacophore that a hexapeptide such as GHRP-6 presents through its folded backbone. The indoline nitrogen carries a methanesulfonyl group and the piperidine nitrogen carries the acyl side chain.
That side chain is a 2-amino-2-methylpropanamide bearing an O-benzyl-D-serine unit. The D configuration at the serine centre is not incidental: the enantiomer is substantially less active, so stereochemical purity is part of the identity specification and not a refinement. The benzyl ether provides the aromatic contact that the peptide secretagogues supply with a tryptophan side chain, and the gem-dimethyl amide caps the chain and blocks amide hydrolysis.
As a small molecule the compound behaves differently from the peptides in the same functional class. It is poorly soluble in water as the free base and is normally handled as the methanesulfonate salt, which dissolves in aqueous buffer at working concentrations and in dimethyl sulfoxide for stock preparation. It has no peptide bonds to cleave, so peptidase-containing media do not degrade it, and it is characterised by HPLC with ultraviolet detection and by mass spectrometry at m/z 529 for the free base. Purity figures quoted against the salt and against the free base differ by roughly eighteen per cent by mass, which is the usual source of disagreement between certificates.
Mechanism of action
GHS-R1a is a class A G protein-coupled receptor coupled principally to Gq. Agonist binding activates phospholipase C beta, which cleaves phosphatidylinositol 4,5-bisphosphate into inositol trisphosphate and diacylglycerol, releasing calcium from intracellular stores and activating protein kinase C. In pituitary somatotroph culture the readouts are intracellular calcium flux by fluorescent indicator, inositol phosphate accumulation, and growth hormone in the medium by ELISA. The compound acts as a full agonist in these assays and is commonly used as the positive control against which peptide secretagogues are ranked.
Two properties make it useful as a tool compound. GHS-R1a shows high constitutive activity, and the receptor’s basal signalling can be separated from agonist-driven signalling using inverse agonists, so a well-behaved full agonist is needed to define the top of the response window. Second, the receptor operates on a pathway parallel to the growth hormone releasing hormone receptor on the same cell type, and combining a GHS-R1a agonist with a GHRHR agonist gives a response larger than either alone, which is the standard demonstration that the two receptors converge on separate second messengers. The compound also shows activity at the receptor expressed in hypothalamic and hippocampal neuronal preparations, where calcium imaging and electrophysiology are the usual readouts.
Research applications
- GHS-R1a functional assays in transfected HEK293 or CHO lines: calcium mobilisation, inositol phosphate accumulation and beta-arrestin recruitment.
- Pituitary somatotroph culture, used as the reference full agonist against ghrelin and the peptide secretagogues.
- Constitutive activity and inverse agonism studies at GHS-R1a, defining the agonist window.
- Receptor cross-talk experiments pairing GHS-R1a with the growth hormone releasing hormone receptor on the same preparation.
- Radioligand and fluorescent ligand displacement binding at GHS-R1a membrane preparations.
- Analytical method development for non-peptide secretagogues, separating the D and L serine diastereomers.
Compounds acting on this axis sit in NuVion’s Growth Hormones category.
Handling in the laboratory
Material of this class is a solid at room temperature and is dissolved into solvent, not reconstituted from a lyophilised cake. Stocks are normally made in dimethyl sulfoxide because free base solubility in water is low, then diluted into aqueous buffer immediately before use, with the final solvent concentration matched in a vehicle control. Where the methanesulfonate salt is used, direct dissolution in aqueous buffer is possible at working concentrations. Solutions are checked for precipitation after dilution, since the compound can come out of solution when a concentrated organic stock meets an aqueous medium.
Solid material is kept sealed, dry and protected from light, refrigerated where the supplier documentation specifies. Stock solutions in dimethyl sulfoxide are aliquoted and frozen so that repeated freeze-thaw cycles are avoided, and the solvent is kept anhydrous because absorbed water lowers the solubility of the free base. Identity and purity are established by HPLC with ultraviolet detection and by mass spectrometry, and any certificate is read carefully for whether the stated purity and content refer to the salt or to the free base.
Testing and supply from NuVion
The compounds NuVion supplies at this receptor are the peptide secretagogues ipamorelin, GHRP-2 and GHRP-6, in the Growth Hormones category. Each is manufactured at a GMP-audited facility and independently tested by Janoshik Analytical, with purity determined by RP-HPLC and identity confirmed by mass spectrometry. Certificates of Analysis for tested batches are published on the product pages and in the COA library. The non-peptide small molecule is not part of the current range.
Related compounds
Peptide agonists at the same receptor include ipamorelin, GHRP-2 and GHRP-6. Compounds acting on the parallel GHRH receptor include sermorelin and CJC-1295.
Frequently asked questions
Is MK-677 a peptide?
No. It is a non-peptide small molecule built on a spiro-indoline piperidine scaffold. It acts at the same receptor as the peptide secretagogues but contains no amide backbone, so peptidases do not degrade it and it is handled as a small molecule in the laboratory.
Why do certificates quote two different molecular weights?
The free base is 528.7 g/mol and the methanesulfonate salt is 624.8 g/mol. Content and purity figures calculated against one and reported against the other differ by roughly eighteen per cent, so the salt form on the certificate is checked before concentrations are calculated.
What is the difference between MK-677 and ibutamoren?
They are the same compound. Ibutamoren is the international non-proprietary name and MK-677 is the original development code. Ibutamoren mesylate refers specifically to the methanesulfonate salt.
Is MK-677 a therapeutic good in Australia?
No. Compounds of this class are laboratory chemicals for in vitro research. MK-677 is not included in the Australian Register of Therapeutic Goods, has not been assessed by the Therapeutic Goods Administration, and is not for human or veterinary use.
Research use only. The compound described on this page is discussed as a laboratory chemical used in in vitro research. It is not included in the Australian Register of Therapeutic Goods and has not been assessed by the Therapeutic Goods Administration for quality, safety or efficacy. It is not for human or veterinary use, and nothing on this page is a representation about therapeutic use.
