Milestones in the discovery of ghrelin*
| Date | Ghrelin |
|---|---|
| *Data until 1996 compiled from the reviews of Bowers2 and Casanueva and Dieguez.15 Items related to motilin are in italics. The discovery date of motilin has also been added. | |
| 1971 | Motilin discovered using as bioassay the contractile effect of extracts of the duodenal mucosa from pigs on the canine stomach. |
| 1976 | In analogy with the release mechanism of other pituitary hormones, growth hormone releasing hormone (GHRH) is postulated to exist. Because enkephalins are weak releasers of growth hormone, it is proposed that GHRH may be structurally related to enkephalins. |
| 1977 | Analogues of enkephalins lacking opiate activity, but with enhanced potency to release growth hormone, are developed. They are referred to as growth hormone secretagogues (GHS). |
| 1982 | GHRH is isolated. Interest in GHSs declines. |
| 1984 | Synthesis of the GHS peptide GHRP-6, a potent releaser of growth hormone. |
| 1984 | It becomes clear that GHSs act via a receptor other than GHRH. Interest in GHS increases again. |
| 1993 | The first non-peptide GHS, L-692,429, is developed by Merck. |
| 1995 | Development of a more potent and orally active GHS, L-163,191 (MK-0677). |
| 1996 | Cloning of the GHS receptor (GHS-R) using expression cloning and MK-0677 as agonist. |
| 1997 | Two receptors related to GHS-R are cloned and named GPR38 and GPR39. Their ligand/agonist is unknown.14 |
| 1998 | A patent is submitted for “motilin homologues”. Much later it will be realised that it is related to ghrelin. |
| 1999, July | Orphan receptor GPR38 is identified as the motilin receptor and renamed MTL-R1a. It is predicted that the natural ligand for GHS-R could be related to motilin. |
| 1999, December | Ghrelin discovered using the Ca response of a cell line expressing GHS-R and isolated from extracts of the rat stomach. |
| 2000, August | Ghrelin “re-discovered” as “motilin related peptide”. |