title: Suppression of rat and human growth hormone and prolactin secretion by a novel somatostatin/dopaminergic chimeric ligand.
abstract: As cotreatment of somatostatin (SRIF) and dopamine (DA) agonists reduces GH in acromegaly more effectively than either agonist alone, SRIF and DA receptors (SSTR and DAR) may interact with enhanced functional activity. The selective SSTR2 agonist, BIM-23023 (50% effective dose, 0.42), and the DAR2 agonist, BIM-53097 (50% effective dose, 22.1), dose- dependently inhibited GH secretion in cultured primary rat and human fetal as well as in human pituitary tumor cells derived from GH-secreting adenomas. The combination of individual SSTR2 and DAR2 agonists was additive for suppressing GH secretion in both rat and human pituitary cells. BIM-23A387 is a chimeric compound that contains structural elements of both SRIF and DA in a single molecule and retains potent, selective binding to DAR2 and SSTR2. BIM-23A387 (50% effective dose, 0.16 for SSTR2 and 24.5 for DAR2), displayed similar efficacy in suppressing GH secretion from rat pituitary cells as the combination of the two individual agonists. In contrast, the chimeric molecule was more potent than individual selective analogs in suppressing GH secretion by human fetal pituitary and GH-secreting adenoma cells (P < 0.05). Although the DAR2 antagonist, sulpiride, reversed BIM-23A387-induced GH suppression, blockade of SSTR2 by the selective SSTR antagonist, BIM-23454, did not block BIM-23A387-suppressed GH secretion. These results indicate that mechanisms by which the chimeric molecule suppresses pituitary GH secretion may not be mediated by individual SSTR2 or DAR2 signaling, respectively. Functional interaction of the two receptors may explain the clinical observation that more effective GH suppression is achieved when DAR2 and SSTR2 agonists are administered in combination. The SRIF/DA chimeric molecule, BIM-23A387, represents a novel tool for effective drug treatment of acromegaly and for prolactinomas otherwise resistant to dopaminergic therapy.
authors: Cedars-Sinai Research Institute, University of California School of Medicine, Los Angeles, California 90048, USA.
authors: Song-Guang
authors: SG
authors: Ren
authors: Sun
authors: S
authors: Kim
authors: John
authors: J
authors: Taylor
authors: Josse
authors: J
authors: Dong
authors: Jacques-Pierre
authors: JP
authors: Moreau
authors: Michael D
authors: MD
authors: Culler
authors: Shlomo
authors: S
authors: Melmed
mesh_terms: D000818:Animals; D018491:Dopamine Agonists / Q000494:pharmacology*; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D010456:Peptides, Cyclic / Q000494:pharmacology; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects; D010911:Pituitary Neoplasms; D011388:Prolactin / Q000378:metabolism*; D015175:Prolactinoma; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000819:agonists; D017481:Receptors, Somatostatin / Q000819:agonists*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
chemical_list: C470245:BIM 23023; D018491:Dopamine Agonists; D008024:Ligands; D010456:Peptides, Cyclic; D017448:Receptors, Dopamine D2; D017481:Receptors, Somatostatin; D011993:Recombinant Fusion Proteins; D019382:Human Growth Hormone; D011388:Prolactin; C093733:somatostatin receptor 2