Biomedical subjects
Publications and source records attributed to Dennis Norman.
We have modified the previously reported 2-aminoquinoline 1 to provide two novel series of MCH-1R antagonists. Representative compounds from the quinazoline and benzimidazole series have been shown to be potent and selective, with promising in vitro eADME profiles.
A new series of 2-aminoquinolines has been identified as antagonists of the melanin concentrating hormone receptor (MCH-1R). Syntheses and structure-activity relationships are described leading to a compound having low nanomolar activity against the receptor and demonstrating functional antagonism. Studies also showed that some of the compounds were selective against a range of other G protein-coupled receptors.
Melanin-concentrating hormone (MCH) has been known to be an appetite-stimulating peptide for a number of years. However, it is only recently that MCH has been discovered to be the natural ligand for a previously "orphan" G-protein-coupled receptor, now designated MCH-1R. This receptor has been shown to mediate the effects of MCH on appetite and body weight, and consequently, drug discovery programs have begun to exploit this information in the search for MCH-1R antagonists for the treatment of obesity. In this paper, we report the rapid discovery of multiple, structurally distinct series of MCH-1R antagonists using a variety of virtual screening techniques. The most potent of these compounds (12) demonstrated an IC(50) value of 55 nM in the primary screen and exhibited antagonist properties in a functional cellular assay measuring Ca(2+) release. More potent compounds were identified by follow-up searches around the initial hit. A proposed binding mode for compound 12 in a homology model of the MCH-1R is also presented.
Leptin is the 167 amino-acid protein product of the Lep (obese) gene that is released predominantly from adipose tissue and circulates at levels related to the amount of fat. Leptin expression is hormonally regulated: insulin and glucocorticoids are stimulators, while inhibitors include beta-adrenergic agonists and testosterone. Recently, adenylate cyclase-coupled melanocortin receptors have been identified in murine adipose tissue, the 3T3-L1 adipocyte cell line, and in human fat tissue. These studies prompted us to evaluate the effects of pro-opiomelanocortin (POMC)-derived peptides on leptin production and expression in 3T3-L1 adipocytes in culture. 3T3-L1 pre-adipocytes differentiated by the insulin/indomethacin (I/I) method produced leptin at levels that were two times higher than those obtained in cells differentiated by the more traditional insulin/dexamethasone/isobutylmethylxanthine (I/D/M) method. By RT-PCR studies, 3T3-L1 cells expressed both the melanocortin 2 receptors (MC2-R) and melanocortin 5 receptors (MC5-R) isoforms of the melanocortin receptor at an early stage of differentiation. When I/I differentiated 3T3-L1 adipocytes were incubated with different concentrations of dibutyryl cAMP (db-cAMP) or POMC-derived peptides (ACTH and alpha-MSH), ACTH and alpha-MSH stimulated cAMP production after 30 min (2-fold increase) associated with a dose-dependent inhibition of leptin secretion (ACTHz.Gt;alpha-MSH; IC(50)=3.2+/-0.4 SE and 36+/-5 nM, respectively), maximal after 3 h of incubation (30% inhibition). In addition, 100 nM ACTH and alpha-MSH induced a 60% reduction in leptin expression by RT-PCR. Incubation of cells with 0.5 mM db-cAMP led to a more prominent inhibition of leptin expression and secretion (up to 80% at 1 and 24 h, respectively). The ACTH and alpha-MSH inhibitory effects on leptin secretion were mediated by activation of the MC2-R and MC5-R and were reversed by the MC-R antagonists ACTH(11-24) and ACTH(7-38). In summary, we have shown that POMC-peptides are potent inhibitors of leptin expression and production in 3T3-L1 adipocytes. The finding of ACTH/alpha-MSH receptor-induced inhibition of leptin production and expression in adipocytes support the possibility that there is a control mechanism for modulation of adipose tissue function via a melanocortin-leptin axis.
We made psychiatric and intellectual assessments of 140 children with attention deficit hyperactivity disorder (ADHD), 120 normal controls, and their 303 siblings. The index children were white, non-Hispanic boys. ADHD children were more likely to have had learning disabilities, repeated grades, been placed in special classes, and received academic tutoring. They also did worse on the Wechsler Intelligence Scale for Children--Revised (WISC-R). Among ADHD probands, comorbid conduct, major depressive, and anxiety disorders predicted school placement more than school failure or WISC-R scores. However, the neuropsychological disability of all ADHD children could not be attributed to comorbid disorders because those without comorbidity had more school failure and lower WISC-R scores than normal controls. Intellectual impairment was also increased among siblings of ADHD children. This provides converging evidence that the ADHD syndrome is familial.