Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 15 de 15
Filter
Add more filters










Publication year range
3.
Bioorg Med Chem Lett ; 17(13): 3657-9, 2007 Jul 01.
Article in English | MEDLINE | ID: mdl-17482461

ABSTRACT

During an effort to search for more potent growth hormone secretagogues, we discovered a class of compounds of which the best compound 8 was 7-fold more active in vitro than the best compound in the series we revealed before [Tata, J. R.; Lu, Z.; Jacks, T. M.; Schleim, K. D.; Cheng, K.; Wei, L.; Chan, W.-S.; Butler, B.; Tsou, N.; Leung, K.; Chiu, S.-H. L.; Hickey, G. J.; Smith, R. G.; Patchett, A. A. Bioorg. Med. Chem. Lett.1997, 7, 2319.]. Animal studies show that compound 8 can stimulate growth hormone release at the oral dose as low as 0.06 mpk. Chemistry and biological studies are discussed.


Subject(s)
Chemistry, Pharmaceutical/methods , Growth Hormone/chemistry , Growth Hormone/chemical synthesis , Administration, Oral , Amides/chemistry , Amines/chemistry , Animals , Dogs , Drug Design , Drug Evaluation, Preclinical , Growth Hormone/metabolism , Indoles/pharmacology , Models, Chemical , Pituitary Gland/chemistry , Pituitary Gland/cytology , Pituitary Gland/drug effects , Rats , Spiro Compounds/pharmacology , Structure-Activity Relationship
4.
Endocrinology ; 147(10): 4664-73, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16857751

ABSTRACT

Somatostatin inhibits both glucagon and insulin secretion. Glucagon significantly contributes to hyperglycemia in type 2 diabetes. Despite its function in the inhibition of glucagon secretion, somatostatin fails to reduce hyperglycemia in type 2 diabetes, due to a parallel suppression of insulin secretion. Five pharmacologically distinct somatostatin receptor subtypes (sst(1)-sst(5)) mediate the effects of somatostatin on a cellular level. Pancreatic A cells express sst(2), whereas B cells express sst(5). In this study, we describe a novel approach to the treatment of type 2 diabetes using a highly sst(2)-selective, nonpeptide agonist (compound 1). Compound 1 effectively inhibited glucagon secretion from pancreatic islets isolated from wild-type mice, whereas glucagon secretion from sst(2)-deficient islets was not suppressed. Compound 1 did not influence nonfasted insulin concentration. In sst(2)-deficient mice, compound 1 did not have any effects on glucagon or glucose levels, confirming its sst(2) selectivity. In animal models of type 2 diabetes in the nonfasted state, circulating glucagon and glucose levels were decreased after treatment with compound 1. In the fasting state, compound 1 lowered blood glucose by approximately 25%. In summary, small-molecule sst(2)-selective agonists that suppress glucagon secretion offer a novel approach toward the development of orally bioavailable drugs for treatment of type 2 diabetes.


Subject(s)
Hypoglycemic Agents/pharmacology , Receptors, Somatostatin/agonists , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Dogs , Glucagon/metabolism , Growth Hormone/metabolism , In Vitro Techniques , Insulin/metabolism , Insulin/pharmacology , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Obese , Rats , Receptors, Somatostatin/genetics
5.
6.
Peptides ; 26(10): 2017-25, 2005 Oct.
Article in English | MEDLINE | ID: mdl-15993513

ABSTRACT

The melanocortin subtype-4 receptor (MC4R) has been implicated in the control of feeding behavior and body weight regulation. A series of tetrapeptides, based on Tic-DPhe-Arg-Trp-NH2-a mimic of the putative message sequence "His-Phe-Arg-Trp" and modified at the DPhe position, were prepared and pharmacologically characterized for potency and selectivity. Substitution of His with Tic gave peptides with significant increases in selectivity. The effects of the substitution pattern of DPhe were investigated and it has significant influences on potency and the level of the maximum cAMP accumulation. Intracerebroventricular administration of peptide 10 induced significant inhibition of cumulative overnight food intake and feeding duration in rats.


Subject(s)
Appetite Depressants/administration & dosage , Appetite Depressants/chemical synthesis , Eating/drug effects , Oligopeptides/administration & dosage , Oligopeptides/chemical synthesis , Receptor, Melanocortin, Type 4/metabolism , Animals , Appetite Depressants/metabolism , Binding, Competitive , CHO Cells , Cricetinae , Cricetulus , Eating/physiology , Humans , Male , Models, Molecular , Oligopeptides/metabolism , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 15(15): 3501-5, 2005 Aug 01.
Article in English | MEDLINE | ID: mdl-15982875

ABSTRACT

A novel isoquinuclidine containing selective melanocortin subtype-4 receptor small molecule agonist, 3 (RY764), is reported. Its in vivo characterization revealed mechanism-based food intake reduction and erectile activity augmentation in rodents.


Subject(s)
Aza Compounds/pharmacology , Eating/drug effects , Penile Erection/drug effects , Piperazines/pharmacology , Piperidines/pharmacology , Receptor, Melanocortin, Type 4/agonists , Animals , Aza Compounds/chemical synthesis , Humans , Male , Microsomes, Liver/metabolism , Piperazines/chemistry , Piperidines/chemical synthesis , Protein Binding , Quinuclidines/chemistry , Rats , Rats, Sprague-Dawley , Rodentia , Structure-Activity Relationship , Time Factors
9.
Bioorg Med Chem Lett ; 15(8): 1993-6, 2005 Apr 15.
Article in English | MEDLINE | ID: mdl-15808454

ABSTRACT

We report the discovery and optimization of substituted 2-piperazinecarboxamides as potent and selective agonists of the melanocortin subtype-4 receptor. The 5- and 6-alkylated piperazine compounds exhibit low bioactivation potential as measured by covalent binding in microsome preparations.


Subject(s)
Piperazines/chemistry , Piperazines/pharmacology , Receptor, Melanocortin, Type 4/agonists , Humans , Piperazines/metabolism , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity Relationship
11.
Bioorg Med Chem Lett ; 13(10): 1817-20, 2003 May 19.
Article in English | MEDLINE | ID: mdl-12729672

ABSTRACT

A new series of growth hormone secretagogues have been discovered. The best compound, 26j, shows excellent ability to release growth hormone both in vitro and in vivo. The synthesis and biological activity of these compounds are discussed.


Subject(s)
Growth Hormone/metabolism , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Administration, Oral , Animals , Biological Availability , Dogs , Growth Hormone/analysis , Piperidines/pharmacology , Pituitary Gland/cytology , Rats , Structure-Activity Relationship
13.
J Med Chem ; 45(21): 4589-93, 2002 Oct 10.
Article in English | MEDLINE | ID: mdl-12361385

ABSTRACT

Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic and to stimulate erectile activity. We report the design and development of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4 receptor. Pharmacological testing confirms the food intake lowering effects of MC4R agonism and suggests another role for the receptor in the stimulation of erectile activity.


Subject(s)
Isoquinolines/chemical synthesis , Receptors, Corticotropin/agonists , Tetrahydroisoquinolines , Triazoles/chemical synthesis , Animals , Binding, Competitive , Biological Availability , CHO Cells , Cricetinae , Dogs , Eating/drug effects , Humans , Isoquinolines/chemistry , Isoquinolines/pharmacology , Molecular Conformation , Penile Erection/drug effects , Rats , Receptor, Melanocortin, Type 3 , Receptor, Melanocortin, Type 4 , Receptors, Melanocortin , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacology
14.
Proc Natl Acad Sci U S A ; 99(17): 11381-6, 2002 Aug 20.
Article in English | MEDLINE | ID: mdl-12172010

ABSTRACT

By using a combination of genetic, pharmacological, and anatomical approaches, we show that the melanocortin 4 receptor (MC4R), implicated in the control of food intake and energy expenditure, also modulates erectile function and sexual behavior. Evidence supporting this notion is based on several findings: (i) a highly selective non-peptide MC4R agonist augments erectile activity initiated by electrical stimulation of the cavernous nerve in wild-type but not Mc4r-null mice; (ii) copulatory behavior is enhanced by administration of a selective MC4R agonist and is diminished in mice lacking Mc4r; (iii) reverse transcription (RT)-PCR and non-PCR based methods demonstrate MC4R expression in rat and human penis, and rat spinal cord, hypothalamus, brainstem, pelvic ganglion (major autonomic relay center to the penis), but not in rat primary corpus smooth muscle cavernosum cells; and (iv) in situ hybridization of glans tissue from the human and rat penis reveal MC4R expression in nerve fibers and mechanoreceptors in the glans of the penis. Collectively, these data implicate the MC4R in the modulation of penile erectile function and provide evidence that MC4R-mediated proerectile responses may be activated through neuronal circuitry in spinal cord erectile centers and somatosensory afferent nerve terminals of the penis. Our results provide a basis for the existence of MC4R-controlled neuronal pathways that control sexual function.


Subject(s)
Copulation/physiology , Penis/physiology , Receptors, Corticotropin/physiology , Sexual Behavior, Animal/physiology , Animals , Blood Pressure/physiology , DNA Primers , DNA, Complementary , Electric Stimulation , Energy Metabolism/physiology , Feeding Behavior/physiology , In Situ Hybridization , In Vitro Techniques , Intracranial Pressure/physiology , Male , Mice , Mice, Inbred C57BL , Models, Animal , Nerve Fibers/physiology , Penis/innervation , Receptor, Melanocortin, Type 4 , Receptors, Corticotropin/genetics , Reverse Transcriptase Polymerase Chain Reaction , Ribonuclease, Pancreatic
SELECTION OF CITATIONS
SEARCH DETAIL
...