Discovery of a non-peptide small molecule that selectively mimics the biological actions of calcitonin

Calcitonin (CT), a 32-amino acid peptide hormone secreted mainly from the t hyroid gland, plays an important role in maintaining bone homeostasis. To d iscover non-peptide small molecules with biological actions similar to thos e of CT, a cell-based screening of an in-house chemical library was perform ed and a pyridone derivative (SUN B8155) was identified. Like CT; it elevat ed cyclic AMP (cAMP) levels in T47D and UMR106-06 sells which endogenously express human and rat CT receptor, respectively. SUN B8155 also stimulated cAMP formation in cells expressing recombinant human CT receptor, but not i n those expressing human parathyroid hormone/parathyroid hormone-related pe ptide receptor. Accumulation of cAMP in T47D cells was blocked by a selecti ve antagonist of CT receptor, salmon CT(8-32), whereas SUN B8155 did not di splace the specific binding of [I-125]CT to the receptor. Our results sugge sted that the compound selectively interacts with the CT receptor by a mech anism similar to but probably different from that of CT itself. In rats, in traperitoneal administration of SUN B8155 significantly lowered serum calci um levels, like CT. Our results demonstrate, for the first time, that the b iological activities of the newly identified small molecule can mimic that of CT, acting via the CT receptor. (C) 2001 Elsevier Science B.V. All right s reserved.