Biomedical subjects

John J Harrington

Publications and source records attributed to John J Harrington.

6 recordsLinked to original sources

PubMed2005

Identification of novel and improved antimitotic agents derived from noscapine.

Analogues of the natural product noscapine were synthesized and their potential as antitumor agents evaluated. The discovery of a novel regioselective O-demethylation facilitated the synthesis of the potent aniline 6, which arrests mammalian cells in the G2/M phase of the cell cycle at 0.1 microM and also affects tubulin polymerization. Aniline 6 is orally bioavailable and is 250-fold more potent than noscapine in reducing cell proliferation in rapidly dividing cells.

Animals↗

PubMed2005

Identification of a novel extracellular cation-sensing G-protein-coupled receptor.

The C family G-protein-coupled receptors contain members that sense amino acid and extracellular cations, of which calcium-sensing receptor (CASR) is the prototypic extracellular calcium-sensing receptor. Some cells, such as osteoblasts in bone, retain responsiveness to extracellular calcium in CASR-deficient mice, consistent with the existence of another calcium-sensing receptor. We examined the calcium-sensing properties of GPRC6A, a newly identified member of this family. Alignment of GPRC6A with CASR revealed conservation of both calcium and calcimimetic binding sites. In addition, calcium, magnesium, strontium, aluminum, gadolinium, and the calcimimetic NPS 568 resulted in a dose-dependent stimulation of GPRC6A overexpressed in human embryonic kidney cells 293 cells. Also, osteocalcin, a calcium-binding protein highly expressed in bone, dose-dependently stimulated GPRC6A activity in the presence of calcium but inhibited the calcium-dependent activation of CASR. Coexpression of beta-arrestins 1 and 2, regulators of G-protein signaling RGS2 or RGS4, the RhoA inhibitor C3 toxin, the dominant negative Galpha(q)-(305-359) minigene, and pretreatment with pertussis toxin inhibited activation of GPRC6A by extracellular cations. Reverse transcription-PCR analyses showed that mouse GPRC6A is widely expressed in mouse tissues, including bone, calvaria, and the osteoblastic cell line MC3T3-E1. These data suggest that in addition to sensing amino acids, GPRC6A is a cation-, calcimimetic-, and osteocalcin-sensing receptor and a candidate for mediating extracellular calcium-sensing responses in osteoblasts and possibly other tissues.

Allosteric Site↗

PubMed2005

Discovery of S-phase arresting agents derived from noscapine.

Analogues of the natural product noscapine were synthesized, and their potential as antitumor agents were examined. The discovery of a novel regio- and stereoselective O-demethylation led to the synthesis of several O-alkylated analogues that induced an unexpected S-phase arrest of mammalian cells. Compound 4a was the most potent analogue inhibiting cell proliferation at an EC(50) of 1.9 microM.

Antineoplastic Agents↗

PubMed2005

Isosteric ramatroban analogs: selective and potent CRTH-2 antagonists.

The chemoattractant receptor-homologous molecule expressed on T(H)2 cells (CRTH-2), also found on eosinophils and basophils, is a prostaglandin D2 receptor involved in the recruitment of these cell types during an inflammatory response. In this report, we describe the synthesis and optimization of a ramatroban isostere that is a selective and potent antagonist of CRTH-2 which may be useful in the treatment of certain diseases.

Anti-Asthmatic Agents↗

PubMed2005

High-throughput target discovery using cell-based genetics.

High-throughput target discovery requires robust disease models and the ability to rapidly survey the genome for function. In the post-genomics era, there has been a strong emphasis placed upon "gene-to-function" approaches that take advantage of the large amount of gene sequence information now available. Here, we advocate a return to "function-to-gene" approaches as a first step in target discovery (and validation), followed by hypothesis-driven research to validate new targets identified by their activity in cell-based disease models.

Animals↗

PubMed2005

Treatment of sleep disorders in elderly patients.

Sleep disorders are common among the elderly and are associated with diminished quality of life, increased risk for development of psychiatric disorders, inappropriate use of sleep aids, and decreased daytime functioning. The most common and important sleep disorders in the elderly include insomnia, obstructive sleep apnea syndrome, restless legs syndrome, rapid eye movement sleep behavior disorder, and the advanced sleep phase syndrome. In this article, we summarize the current treatment strategies for each of these sleep-related disorders. Before contemplating specific treatments, the authors recommend that more conservative and nonpharmacologic therapies be attempted first because the elderly are more likely to have medication side effects or complications related to surgery. Many sleep problems can be treated by simple sleep hygiene modifications that can be implemented and adopted easily. For others, therapies that specifically consider older adults may be required. For each of the sleep disorders we provide an updated discussion of therapies beginning with diet and lifestyle, pharmacologic treatment, interventional procedures, surgery, assistive devices, physical and speech therapy, exercise, and emerging therapies with specific considerations for older adults.

Journal Article↗