Biomedical subjects

William Thomsen

Publications and source records attributed to William Thomsen.

5 recordsLinked to original sources

PubMed2005

Functional assays for screening GPCR targets.

G-protein-coupled receptors (GPCRs) are valuable molecular targets for drug discovery. An important aspect of the early drug discovery process is the design and implementation of high-throughput GPCR functional assays that allow the cost-effective screening of large compound libraries to identify novel drug candidates. Several functional assay kits based on fluorescence and/or chemiluminescence detection are commercially available for convenient screen development, each having advantages and disadvantages. In addition, new GPCR biosensors and high-content imaging technologies have recently been developed that hold promise for the development of functional GPCR screens in living cells.

Animals↗

PubMed2005

Anxiolytic- and antidepressant-like profile of ATC0065 and ATC0175: nonpeptidic and orally active melanin-concentrating hormone receptor 1 antagonists.

Melanin-concentrating hormone (MCH) is a cyclic peptide produced in the lateral hypothalamus. It has been implicated in a number of physiological processes including feeding behavior, energy balance, and the regulation of emotional states. Here, we report in vitro and in vivo profiles of ATC0065 [N(2)-[cis-4-({2-[4-bromo-2-(trifluoromethoxy)phenyl]ethyl}amino)cyclohexyl]-N(4), N(4)-dimethylquinazoline-2,4-diamine dihydrochloride] and ATC0175 [N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorobenzamide hydrochloride], newly synthesized MCH receptor 1 (MCHR1) antagonists. Both ATC0065 and ATC0175 had high affinities for human MCHR1 with IC(50) values of 15.7 +/- 1.95 and 7.23 +/- 0.59 nM, respectively. Both ATC0065 (IC(50) = 21.4 +/- 1.57 nM) and ATC0175 (IC(50) = 13.5 +/- 0.78 nM) showed potent antagonist activities at MCHR1, as assessed by MCH-increased guanosine 5'-O-(3-[(35)S]thio)phosphate ([(35)S]GTPgammaS) binding to human MCHR1. Oral administration of ATC0065 (3-30 mg/kg) or ATC0175 (1-10 mg/kg) significantly reduced immobility time in the forced swimming test in rats, indicating antidepressant-like effects. Both ATC0065 and ATC0175 significantly reversed swim stress-induced anxiety in the elevated plus-maze test in rats and stress-induced hyperthermia in mice. ATC0175 significantly increased social interaction between unfamiliar rats and reduced separation-induced vocalizations in guinea pig pups, indicating anxiolytic potential. In contrast, ATC0065 and ATC0175 did not affect spontaneous locomotor activity or rotarod performance in rats. These findings indicate that ATC0065 and ATC0175 are potent and orally active MCHR1 antagonists with anxiolytic and antidepressant activity in rodents.

Administration, Oral↗

PubMed2005

ATC0175: an orally active melanin-concentrating hormone receptor 1 antagonist for the potential treatment of depression and anxiety.

Melanin-concentrating hormone (MCH) has been implicated in a variety of physiological events. Recent studies clearly suggest that MCH plays an important role in the regulation of stress and emotion. To date, two receptor subtypes of MCH (MCH1R and MCH2R) have been identified. MCH1R has been suggested to mediate most of the physiological functions of MCH. Recently, we synthesized an orally active, nonpeptidic antagonist of MCH1R, N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorobenzamide hydrochloride (ATC0175). This compound is a potent antagonist with a high affinity for MCH1R and additional affinities for 5-HT1A and 5-HT2B receptors. The receptor binding and the functional assay (MCH-induced increase in [Ca2+]i) indicated that ATC0175 is a noncompetitive antagonist at MCH1Rs. ATC0175 exhibited anxiolytic effects in numerous animal models of anxiety including the elevated plus-maze test, social interaction test, stress-induced hyperthermia and maternal separation-induced vocalization. Like with other stress-related peptide receptor antagonists, such as antagonists of corticotropin-releasing factor or vasopressin V1b receptor antagonists, anxiolytic effects of ATC0175 were more pronounced in models containing a stress component. ATC0175 also exhibited antidepressant effects in the forced swimming test. ATC0175 increased swimming performance without altering climbing behavior, as observed with selective serotonin reuptake inhibitors. ATC0175 has adequate ADME profile (reasonable oral bioavailability and brain penetration) and potent oral activity in animal models. In contrast, ATC0175 did not affect spontaneous locomotor activity, hexobarbital-induced sleeping time and did not impair rotarod performance. Thus, ATC0175 may be devoid of unwanted central nervous system side effects, which are sometimes observed with current medications. In addition, ATC0175 was well tolerated in rat repeated toxicity study, and had no genotoxic liability. Therefore, ATC0175 has the potential to be effective in the treatment of patients with depression and/or anxiety disorders.

Animals↗

PubMed2004

G protein-coupled receptors as therapeutic targets for obesity and type 2 diabetes.

The prevalence of obesity and type 2 diabetes, two strongly correlated disorders, is increasing worldwide. Weight loss can reduce the risk of developing type 2 diabetes and the pharmacological treatments normally required to manage this disorder. Even though dietary and lifestyle changes may eventually reduce obesity for some individuals, new safe and more efficacious drugs are required for successful weight reduction and treatment of type 2 diabetes in a large proportion of obese individuals. In addition to targeting known G protein-coupled receptors (GPCRs), several orphan GPCRs expressed in central nervous system areas known to regulate feeding may provide new targets for the treatment of obesity. Similarly, the pancreas contains numerous islet GPCRs as well as an abundance of orphan GPCRs that potentially could emerge as targets for future antidiabetic compounds. One of the major challenges facing the pharmaceutical industry is how to rapidly establish the function and therapeutic relevance of orphan GPCRs, some of which may represent novel targets for the discovery of the next generation of drugs to effectively treat obesity and type 2 diabetes. This review will focus on the significant potential of known and orphan GPCRs as targets for the discovery of new drugs to successfully treat these serious disorders.

Animals↗

PubMed2004

Orphan GPCR target validation.

Nearly half of the identified non-olfactory G protein-coupled receptors (GPCRs) have no identified cognate ligand. These 'orphan' receptors are likely to have important physiological roles that could potentially be exploited therapeutically. However, by definition, such receptors are not immediately open for pharmacological investigation of their function. Here we summarize several strategic approaches to facilitate the discovery of orphan GPCR biology.

Animals↗