TPT sulfonate, a single, oral dose schistosomicidal prodrug: In vivo efficacy, disposition and metabolic profiling.

Treatment of schistosomiasis relies precariously on just one drug, praziquantel (PZQ). In the search for alternatives, 15 S-[2-(alkylamino)alkane] thiosulfuric acids were obtained from a previous research program and profiled in mice for efficacy against both mature (>42-day-old) and juvenile (21-day-old) Schistosoma mansoni using a screening dose of 100 mg/kg PO QDx4. One compound, S-[2-(tert-butylamino)-1-phenylethane] thiosulfuric acid (TPT sulfonate), was the most effective by decreasing female and male worm burdens by ≥ 90% and ≥46% (mature), and ≥89% and ≥79% (juvenile), respectively.

Myelinated axons fail to develop properly in a genetically authentic mouse model of Charcot-Marie-Tooth disease type 2E.

We have analyzed a mouse model of Charcot-Marie-Tooth disease 2E (CMT2E) harboring a heterozygous p.Asn98Ser (p.N98S) Nefl mutation, whose human counterpart results in a severe, early-onset neuropathy.

PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent models.

Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by duplication of peripheral myelin protein 22 (PMP22) and is the most common hereditary peripheral neuropathy. CMT1A is characterized by demyelination and axonal loss, which underlie slowed motor nerve conduction velocity (MNCV) and reduced compound muscle action potentials (CMAP) in patients. There is currently no known treatment for this disease.

CTSA-IP: a solution to identifying and aggregating intellectual property across the NIH Clinical Translational Science Award (CTSA) consortium of biomedical research institutes.

One of the objectives of the Consortium of Institutions with Clinical and Translational Science Awards (CTSAs) is to enhance technology transfer among the CTSAs and with public and private sector partners. Clinical and Translational Sciences Award Intellectual Property (CTSA-IP; http://www.CTSAIP.

Schwann cell overexpression of the GPR7 receptor in inflammatory and painful neuropathies.

The human 7-transmembrane receptor GPR7 has sequence similarity to opioid and somatostatin receptors, and can be activated by the recently discovered neuropeptides NPB and NPW. This receptor is highly expressed in the nervous system, with suggested roles in neuroendocrine events and pain signaling. In this study, we investigated whether the GPR7 receptor is expressed in the peripheral nervous system under normal and pathological conditions.

Selective expression of regulators of G-protein signaling (RGS) in the human central nervous system.

The human tissue distribution of the nineteen known human regulators of G-protein signaling (RGS) is described. Measurement of RGS mRNA levels in human brain and in nine peripheral tissues revealed striking tissue preferences in gene expression. Five RGS members were identified with enriched expression in brain.

Modification of nociception and morphine tolerance by the selective opiate receptor-like orphan receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111).

(-)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111) is a novel human opiate receptor-like orphan receptor (ORL-1) antagonist that has high affinity for the clonal human ORL-1 receptor (hORL-1 K(i) = 0.33 nM), selectivity versus mu-(174-fold), delta-(6391-fold), and kappa (486-fold)-opioid receptors and is able to inhibit nociceptin signaling via hORL-1 in a whole cell gene reporter assay. SB-612111 has no measurable antinociceptive effects in vivo in the mouse hot-plate test after intravenous administration but is able to antagonize the antimorphine action of nociceptin [ED(50) = 0.

4-Amino-3(2H)-pyridazinones bearing arylpiperazinylalkyl groups and related compounds: synthesis and antinociceptive activity.

A series of 4-amino-3(2H)-pyridazinones substituted at position 2 with arylpiperazinylalkyl groups and analogues were synthesized and their antinociceptive effect was evaluated in the mouse abdominal constriction model. Preliminary SARs studies were performed. Several of the novel compounds dosed at 100 mg/kg s.

Evidence for a selective role of the delta-opioid agonist [8R-(4bS*,8aalpha,8abeta, 12bbeta)]7,10-Dimethyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl 5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride (SB-235863) in blocking hyperalgesia associated with inflammatory and neuropathic pain responses.

The specific involvement of the delta-opioid receptor in the control of nociception was explored by investigating the pharmacological activity in vivo of a selective, orally active, and centrally penetrant delta-opioid agonist. [8R-(4bS*,8aalpha,8abeta,12bbeta)]7,10-dimethyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl 5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride (SB-235863) is a new pyrrolomorphinan with high affinity (Ki = 4.81 +/- 0.

PTH2 receptor-mediated inhibitory effect of parathyroid hormone and TIP39 on cell proliferation.

The parathyroid hormone (PTH) has dual mitogenic and inhibitory effects on cell proliferation, depending on the cell type and experimental conditions. PTH can signal via two different receptors, both positively coupled to the adenylyl cyclase/cyclic AMP pathway which can mimic some of the proliferative effects of PTH. We evaluated the role of the type-2 PTH (PTH2) receptor on cell proliferation in clonal human embryonic kidney HEK293 cells stably expressing the human PTH2 receptor.

Up-regulation of regulator of G protein signaling 4 expression in a model of neuropathic pain and insensitivity to morphine.

We hypothesized that the up-regulated expression of one or more members of the regulator of G protein signaling (RGS) family can cause an attenuation of signaling via Gi/Go-coupled opioid receptors, and thereby play a role in the development of hyperalgesia and accompanying insensitivity to morphine observed in animal models of neuropathic pain. Accordingly, we examined the mRNA expression of several RGS genes in a rat model of chronic neuropathic pain induced by partial ligation of the sciatic nerve. During the development of hyperalgesia, RGS4 was the only isoform examined whose mRNA levels increased significantly (up to 230%) in the lumbar spinal cord.

The novel and systemically active metabotropic glutamate 1 (mGlu1) receptor antagonist 3-MATIDA reduces post-ischemic neuronal death.

We examined the pharmacological properties of 3-methyl-aminothiophene dicarboxylic acid (3-MATIDA) by measuring second messenger responses in baby hamster kidney cells stably transfected with mGlu1a, mGlu2, mGlu4a or mGlu5a receptors and ionotropic glutamate receptor agonist-induced depolarizations in mouse cortical wedges. 3-MATIDA was a potent (IC(50)=6.3 microM, 95% confidence limits 3-15) and relatively selective mGlu1 receptor antagonist.

Side-chain lactam-bridge conformational constraints differentiate the activities of salmon and human calcitonins and reveal a new design concept for potent calcitonin analogues.

We have recently reported the potent hypocalcemic effects of side-chain lactam-bridged analogues of human calcitonin (hCT) (Kapurniotu, A.; et al. Eur.