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.
Georg Thieme Verlag KG Stuttgart · New York.