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Biomedical subjects

Philip S Jones

Publications and source records attributed to Philip S Jones.

9 recordsLinked to original sources
PubMed2007

The hypnotic, electroencephalographic, and antinociceptive properties of nonpeptide ORL1 receptor agonists after intravenous injection in rodents.

BACKGROUND: Agonists at the opioid receptor-like receptor 1 (ORL1) induce motor impairment, sedation, and loss of righting reflex (LRR) in rodents. This receptor may provide a novel target in the field of anesthesia. METHODS: We examined the hypnotic, electroencephalographic (EEG), and antinociceptive effects of two IV administered nonpeptide ORL1 agonists, (Ro 65-6570 and Org 26383), using LRR in mice and rats, percent EEG burst suppression in rats, and formalin paw test in mice. RESULTS: In mice, Ro 65-6570 and Org 26383 produced LRR (hypnotic dose 0.6 and 3.7 micromol/kg for Ro 65-6570 and Org 26383, respectively). Naloxone had no significant effect on sleep times produced by both compounds. In rats, Ro 65-6570 (0.6-2.4 micromol/kg) and Org 26383 (4-8 micromol/kg) produced LRR and burst suppression activity in the EEG. Both sleep times and burst suppression activity were significantly reduced with a selective ORL1 antagonist. In mice, dose-dependent inhibition of formalin-induced nociceptive behaviors occurred (Phase 1 ED50 0.4 and 1.8 micromol/kg and Phase 2 ED50 0.4 and 4.2 micromol/kg for Ro 65-6570 and Org 26383, respectively). CONCLUSIONS: These results show that Ro 65-6570 and Org 26383 (probably via the ORL1 receptor) behave as IV hypnotics and analgesics in mice and rats, and that the hypnotic and antinociceptive doses are similar.

Animals↗
PubMed2006

Synthesis and evaluation of N-3 substituted phenoxypropyl piperidine benzimidazol-2-one analogues as NOP receptor agonists with analgesic and sedative properties.

A series of 3-phenoxypropyl piperidine benzimidazol-2-one analogues have been discovered as novel NOP receptor agonists. Structure-activity relationships have been explored via N-3 substitution of the benzimidazol-2-one with a range of functionality. The N-methyl acetamide derivative (+)-7f was found to be a high-affinity, potent NOP agonist with greater than 100-fold selectivity over the MOP receptor. Furthermore (+)-7f was shown to be both antinociceptive and sedative when administered iv to rodents.

Analgesics↗
PubMed2003

Identification of a novel class of orally active pyrimido[5,4-3][1,2,4]triazine-5,7-diamine-based hypoglycemic agents with protein tyrosine phosphatase inhibitory activity.

A novel series of orally active pyrimido[5,4-3][1,2,4]triazine-5,7-diamine-based hypoglycemic agents have been identified. These compounds show non-selective inhibitory properties against a panel of protein tyrosine phosphatases including PTP1B. Compounds 12 and 13 display oral glucose lowering effects in ob/ob mice.

Administration, Oral↗
PubMed2003

New building blocks for the assembly of sequence selective molecular zippers.

Synthetic H-bonded molecular zippers contain no sequence information that can be used to engineer the selective binding interactions characteristic of biopolymers; reversing the sense of the amide bonds in the two binding partners generates a new orthogonal recognition motif and the mutually complementary binding partners form complexes an order of magnitude more stable than the corresponding mismatch complexes.

Amino Acid Motifs↗
PubMed2003

Discovery of novel low molecular weight inhibitors of IMPDH via virtual needle screening.

Novel, low molecular weight inhibitors of IMPDH have been discovered through the application of a validated virtual screening protocol. A series of 21 IMPDH inhibitors were used to validate the docking procedure. Application of this procedure to the selection of compounds for screening from an in-house database resulted in a 50-fold reduction in the size of the screening set (3425 to 74 compounds) and gave a hit-rate of 10% on biological evaluation.

Binding Sites↗
PubMed2002

Chemical triple-mutant boxes for quantifying cooperativity in intermolecular interactions.

Chemical double-mutant cycles have been used to quantify intermolecular functional-group interactions in H-bonded zipper complexes in chloroform. If the same interaction is measured in zippers of different overall stability, the double-mutant cycles can be combined to produce a triple-mutant box. This construct quantifies cooperativity between the functional group interaction of interest and the other interactions that are used to change the overall stability of the complexes. The sum of two edge-to-face aromatic interactions (-2.9 +/- 0.5 kJ mol-1) is shown to be insensitive to changes of up to 13.7 +/- 0.2 kJ mol-1 in the overall stability of the complex. In principle, enthalpic cooperative effects caused by entropy-enthalpy compensation could perturb the measurement of intermolecular interactions when using the double-mutant cycle approach, but these experiments show that, for this system, the magnitude of the effect lies within the error of the measurements.

Hydrogen Bonding↗