Scientists discovered that adenosine – a molecule found everywhere in the body and also the basis of caffeine – can partially turn on the growth hormone secretagogue receptor (GHS‑R), the same receptor that GHRP‑6 targets. It binds at a different spot than GHRP‑6, and common caffeine‑like drugs (theophylline, XAC) can block this activation. In plain terms, caffeine and related substances might blunt the effects of GHRP‑6 or other GH‑boosting peptides.

The growth hormone secretagogue receptor (GHS-R) is involved in the regulation of pulsatile GH release. However, until recently, natural endogenous ligands for the receptor were unknown. We fractionated porcine hypothalamic extracts and assayed fractions for activity on HEK293 cells expressing GHS-R and aequorin. A partial agonist was isolated and identified using microspray tandem mass spectrometry as adenosine. GHS-R activation by adenosine and synthetic adenosine agonists is inhibited by the GHS-R selective antagonists L-765,867, D-Lys(3)-GHRP-6, and by theophylline and XAC. Cross desensitization of the GHS-R occurs with both MK-0677 and adenosine. Ligand binding and site directed mutagenesis studies show that adenosine binds to a binding site that is distinct from the previously characterized MK-0677 and GHRP-6 binding pocket. We propose, that adenosine is a physiologically important endogenous GHS-R ligand and speculate that GHS-R ligands modulate dopamine release from hypothalamic neurons.