Abstract
A combination of basic research observations concerning the interaction of somatostatin
(SST) and dopamine (DA) receptors, and clinical reports of enhanced efficacy of combined
SST and DA analogue treatment in suppressing GH hypersecretion, lead to the concept
of creating chimeric molecules combining structural features of both compound classes.
The resulting SST/DA chimeras retain the ability to interact with receptors of both
families and display greatly enhanced potency and efficacy, as compared with that
of individual SST or DA receptor agonists. In vitro studies with pituitary adenoma
cells from acromegalic patients have demonstrated that the chimeric molecules have
exceptional activity with regard to suppression of GH and prolactin secretion. Similarly,
potent suppression of ACTH secretion from Cushing’s-causing corticotroph tumors, and
suppression of nonfunctioning pituitary adenoma proliferation has been observed. The
chimeric SST/DA compounds are also quite potent and efficacious in suppressing both
GH and IGF1 in vivo when tested in nonhuman primates, with no effect on either insulin
secretion or glycemic control. Initial clinical studies examining acute, subcutaneous
administration of the chimeric SST/DA compound, BIM-23A760, revealed both prolonged
circulating half-life and extended duration of biological effect. With chronic administration,
however, BIM-23A760 was found to produce a metabolite with dopaminergic activity that
gradually accumulates and interferes with the activity of the parent compound. Consequently,
efforts are currently underway to produce a second-generation chimera for treatment
of neuroendocrine disease.
Key words
acromegaly - growth hormone - adenomas - Cushings - receptor - heterodimer - BIM-23A760
