Ghrelin is a GH-releasing peptide that also has an important role as an orexigenic hormone-stimulating food intake. By measuring inositol phosphate turnover or by using a reporter assay for transcriptional activity controlled by cAMP-responsive elements, the ghrelin receptor showed strong, ligand-independent signaling in transfected COS-7 or human embryonic kidney 293 cells. Ghrelin and a number of the known nonpeptide GH secretagogues acted as agonists stimulating inositol phosphate turnover further. In contrast, the low potency ghrelin antagonist, [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance P was surprisingly found to be a high potency (EC50 = 5.2 nm) full inverse agonist as it decreased the constitutive signaling of the ghrelin receptor down to that observed in untransfected cells. The homologous motilin receptor functioned as a negative control as it did not display any sign of constitutive activity; however, upon agonist stimulation the motilin receptor signaled as strongly as the unstimulated ghrelin receptor. It is concluded that the ghrelin receptor is highly constitutively active and that this activity could be of physiological importance in its role as a regulator of both GH secretion and appetite control. It is suggested that inverse agonists for the ghrelin receptor could be particularly interesting for the treatment of obesity.
Privileged structures are ligand substructures that are widely used to generate high-affinity ligands for more than one type of receptor. To explain this, we surmised that there must be some common feature in the target proteins. For a set of class A GPCRs, we found a good correlation between conservation patterns of residues in the ligand binding pocket and the privileged structure fragments in class A GPCR ligands. A major part of interior surface of the common ligand binding pocket of class A receptors, identified in many GPCRs, is lined with variable residues that are responsible for selectivity in ligand recognition, while other regions, typically located deeper into the binding pocket, are more conserved and retain a predominantly hydrophobic and aromatic character. The latter is reflected in the chemical nature of most GPCR privileged structures and is proposed to be the common feature that is recognized by the privileged structures. Further, we find that this subpocket is conserved even in distant orthologs within the class A family. Three pairs of ligands recognizing widely different receptor types were docked into receptor models of their target receptors utilizing available structure- activity relationships and mutagenesis data. For each pair of ligands, the ligand-receptor complexes reveal that the nature of the privileged structure binding pocket is conserved between the two complexes, in support of our hypothesis. Only part of the privileged structures can be accommodated within the conserved subpocket. Some contacts are established between the privileged structure and the nonconserved parts of the binding pocket. This implies that any one particular privileged structure can target only a subset of receptors, those complementary to the full privileged structure. Our hypothesis leads to a valuable novelty in that ligand libraries can be designed without any foreknowledge of the structure of the endogenous ligand, which in turn means that even orphan receptors can in principle now be addressed as potential drug targets.
The development and pharmacology of a new potent growth hormone (GH) secretagogue, ipamorelin, is described. Ipamorelin is a pentapeptide (Aib-His-D-2-Nal-D-Phe-Lys-NH 2 ), which displays high GH releasing potency and efficacy in vitro and in vivo. As an outcome of a major chemistry programme, ipamorelin was identified within a series of compounds lacking the central dipeptide Ala-Trp of growth hormone-releasing peptide (GHRP)-1.In vitro, ipamorelin released GH from primary rat pituitary cells with a potency and efficacy similar to GHRP-6 (EC 50 ¼ 1.3Ϯ0.4 nmol/l and E max ¼ 85Ϯ5% vs 2.2Ϯ0.3 nmol/l and 100%). A pharmacological profiling using GHRP and growth hormone-releasing hormone (GHRH) antagonists clearly demonstrated that ipamorelin, like GHRP-6, stimulates GH release via a GHRP-like receptor.In pentobarbital anaesthetised rats, ipamorelin released GH with a potency and efficacy comparable to GHRP-6 (ED 50 ¼ 80Ϯ42 nmol/kg and E max ¼ 1545Ϯ250 ng GH/ml vs 115Ϯ36 nmol/kg and 1167Ϯ120 ng GH/ml).In conscious swine, ipamorelin released GH with an ED 50 ¼ 2.3Ϯ0.03 nmol/kg and an E max ¼ 65Ϯ0.2 ng GH/ml plasma. Again, this was very similar to GHRP-6 (ED 50 ¼ 3.9Ϯ1.4 nmol/kg and E max ¼ 74Ϯ7 ng GH/ml plasma). GHRP-2 displayed higher potency but lower efficacy (ED 50 ¼ 0.6 nmol/kg and E max ¼ 56Ϯ6 ng GH/ml plasma).The specificity for GH release was studied in swine. None of the GH secretagogues tested affected FSH, LH, PRL or TSH plasma levels. Administration of both GHRP-6 and GHRP-2 resulted in increased plasma levels of ACTH and cortisol. Very surprisingly, ipamorelin did not release ACTH or cortisol in levels significantly different from those observed following GHRH stimulation. This lack of effect on ACTH and cortisol plasma levels was evident even at doses more than 200-fold higher than the ED 50 for GH release.In conclusion, ipamorelin is the first GHRP-receptor agonist with a selectivity for GH release similar to that displayed by GHRH. The specificity of ipamorelin makes this compound a very interesting candidate for future clinical development.
Demonstration of non-inferiority between MYL-1501D and reference insulin glargine for reduction of HbA1c during 24 weeks of treatment was achieved. The two treatment groups were similar in terms of secondary endpoints, including hypoglycaemia and nocturnal hypoglycaemia, local and systemic reactions, other safety variables, and immunogenicity.
The discovery of novel non-peptide compounds with a high affinity for the peptide hormone somatostatin (SST) receptor is described. The compounds were tested for affinity at five human SST receptor subtypes individually expressed in mammalian cells. The compound NNC 26-9100 showed a K i of 6 nM at SST 4 and more than 100 fold selectivity for SST 4 over SST 1 , SST 2 , SST 3 , or SST 5 . Competition binding studies and Scatchard analysis of the interaction by NNC 26-9100 with SST showed specificity at SST 4 . Furthermore, NNC 26-9100 was highly selective for SST 4 over a variety of other G protein-coupled receptors, having affinities for M 1 muscarinic acetylcholin and D 3 dopamine receptors of around 500 and 1000 nM, respectively. Finally, NNC 26-9100 was found to fully inhibit forskolin-induced accumulation of adenosine 3′,5′-cyclic monophosphate in baby hamster kidney cells, expressing the human SST 4 receptor with an EC 50 of 2 nM.
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