Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of 2-(thioalkyl)pentanedioic acids were synthesized and evaluated as inhibitors of glutamate carboxypeptidase II (GCP II, EC 3.4.17.21). The inhibitory potency of these thiol-based compounds against GCP II was found to be dependent on the number of methylene units between the thiol group and pentanedioic acid. A comparison of the SAR of the thiol-based inhibitors to that of the phosphonate-based inhibitors provides insight into the role of each of the two zinc-binding groups in GCP II inhibition. The most potent thiol-based inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (IC(50) = 90 nM), was found to be orally bioavailable in rats and exhibited efficacy in an animal model of neuropathic pain following oral administration.
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PMID:Synthesis and biological evaluation of thiol-based inhibitors of glutamate carboxypeptidase II: discovery of an orally active GCP II inhibitor. 1272 61

Local pain is a major limiting factor in regional hyperthermia treatment with radiative applicators. Absorbing structures, consisting of agar bound saline water, have been used successfully to reduce peripheral hot spots. However, both clinical experience and simulation results indicate a SAR elevation in the tissue under the edges of the absorber block. This paper investigates the effect of modification of shape, position and spatial composition of the absorber blocks on the central attenuating effect and the SAR elevating effect at the edges. A selection from a set of five options is made based on simulations with a phantom and a single ring dipole applicator. The simulations have been performed with the FDTD core of the regional hyperthermia treatment planning system. It is shown that tapering of the absorber edge and introduction of a water layer between the absorber and the skin can reduce the edge effect in the superficial fat layer by approximately 50% with respect to a rectangular absorber. A further reduction of 15% can be obtained by an absorber with an appropriate gradient of its conductivity in the direction of the dominant E-field. The modified absorbers produce a central attenuating effect comparable to the rectangular type. The use of a water layer type and a sigma gradient type absorber is also analysed in a patient anatomy, both in the dipole ring applicator, operating at 70 MHz, as well as in a three ring Cavity Slot (CS) applicator, operating at 150 MHz. The mutual influence of phase-amplitude steering and the application of absorbers is investigated in the CS applicator. It appears that absorbers have a significant influence on the interference pattern in the patient model, possibly causing substantial reduction of the SAR value in the tumour and limiting the possibility of ad hoc application of absorbers. Re-optimization can only partly cancel this effect. Local SAR reduction by phase-amplitude control alone can match or improve the effect obtained with modified absorbers.
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PMID:Improvement of absorbing structures used in regional hyperthermia. 1475 51

A novel class of 6-aryl-6H-pyrrolo[3,4-d]pyridazine ligands for the alpha2delta subunit of voltage-gated calcium channels has been described. Substitutions in the aryl ring of the molecule were generally not tolerated, and resulted in diminished binding to the alpha2delta subunit. Modifications to the pyridazine ring revealed numerous permissive substitutions, and detailed SAR studies were carried out in this portion of the molecule. Replacement of the pyridazine ring methyl group with an aminomethyl functionality provided greatly improved potency over the initial lead. The initial lead compound displayed good rat pharmacokinetic properties, and was shown to be efficacious in the Chung model for neuropathic pain in rats.
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PMID:Synthesis and biological evaluation of 6-aryl-6H-pyrrolo[3,4-d]pyridazine derivatives: high-affinity ligands to the alpha 2 delta subunit of voltage gated calcium channels. 1498 Jun 85

Access to health care always has been one of the most critical issues for offshore crews. Therefore, telemedicine has a long and outstanding tradition in the maritime environment. Since 1931 Cuxhaven medical center (Medico Cuxhaven) operates as a hospital-based radio medical advice center (RMA) for ships worldwide providing one of the first routine telemedical services worldwide. For a long time this task was performed on a honorary basis by the hospital's physicians. In 1994 Germany accepted the IMO/ILO (International Maritime Organisation and International Labour Organisation) solution 164. Therefore, in 1998 a formal contract of the German Ministry of Transport officially installed Medico Cuxhaven as the TMAS Center for Germany. According to IMO/ILO solution 164, the RMA provides an expert level of care 24 h/day, 365 days/year. Cuxhaven hospital is a busy general hospital with departments of anesthesia and intensive care, internal medicine, surgery, gynecology and obstetrics, urology, pediatrics, ENT, radiology, and pain medicine. All physicians directly responding to TMAS calls have practical experience in maritime routine and emergency medicine. All incoming emergency calls are primarily handled by board-certified anesthesiologists, experienced in martime emergency medicine (e. g., staffing coastal SAR helicopters, working on rescue boats, carrying out repatriation services for sailors worldwide). If needed, other medical specialists are included. Today, Medico Cuxhaven takes an average workload of one to two emergency calls (response time < 20 s), two to three follow-up calls and approximately one informative call per day. Since 2000 transmission of digital photos has been used for routine RMA. Recently, a system for online and trenddata telemetry of twelve-lead ECG, NIBP (noninvasive blood pressure measurement), CO(2), SaO(2), pulse and respiration rates including the transmission of video images was developed. This system allows worldwide communications as it is capable of all possible means of telecommunication such as GSM, Inmarsat-ISDN or Iridium-Satellite-Transmission. So far, this system has been installed on board several German SAR rescue boats.However, radio telephone and the simple transmission of digital photography remain the basis of maritime radio medical advice service.
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PMID:[Telemedicine in the maritime environment--hightech with a fine tradition]. 1502 90

Noncompetitive antagonists of the human metabotropic glutamate receptor subtype 5 (mGluR5) have been implicated as potential therapeutics for the treatment of a variety of nervous system disorders, including pain, anxiety, and drug addiction. To discover novel noncompetitive antagonists to the mGluR5, we initiated an SAR study around the known lead compounds MPEP and M-MPEP. Our results pointed out the critical role of the para position of the two aromatic rings, which leads to inactive products and permitted the discovery of potent mGluR5 antagonists (e.g., 16, 25, 28, 34 IC(50) = 13.5, 11.9, 21, 15 nM, respectively).
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PMID:Synthesis and receptor assay of aromatic-ethynyl-aromatic derivatives with potent mGluR5 antagonist activity. 1558 65

SAR (structure-activity relationship) studies of triazafluorenone derivatives as potent mGluR1 antagonists are described. The triazafluorenone derivatives are non-amino acid derivatives and noncompetitive mGluR1 antagonists that bind at a putative allosteric recognition site located within the seven-transmembrane domain of the receptor. These triazafluorenone derivatives are potent, selective, and systemically active mGluR1 antagonists. Compound 1n, for example, was a very potent mGluR1 antagonist (IC50 = 3 nM) and demonstrated full efficacy in various in vivo animal pain models.
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PMID:Structure-activity relationship of triazafluorenone derivatives as potent and selective mGluR1 antagonists. 1627 97

A series of thiol-based inhibitors containing a benzyl moiety at the P1' position have been synthesized and tested for their abilities to inhibit glutamate carboxypeptidase II (GCP II). 3-(2-Carboxy-5-mercaptopentyl)benzoic acid 6c was found to be the most potent inhibitor with an IC(50) value of 15 nM, 6-fold more potent than 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA), a previously discovered, orally active GCP II inhibitor. Subsequent SAR studies have revealed that the phenoxy and phenylsulfanyl analogues of 6c, 3-(1-carboxy-4-mercaptobutoxy)benzoic acid 26a and 3-[(1-carboxy-4-mercaptobutyl)thio]benzoic acid 26b, also possess potent inhibitory activities toward GCP II. In the rat chronic constriction injury (CCI) model of neuropathic pain, compounds 6c and 26a significantly reduced hyperalgesia following oral administration (1.0 mg/kg/day).
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PMID:Structural optimization of thiol-based inhibitors of glutamate carboxypeptidase II by modification of the P1' side chain. 1668 31

The preliminary SAR of a series of novel 1,5-biaryl pyrrole EP1 receptor antagonists derived from compound 1 is described. Replacement of the benzyl group of 1 with isosteric groups was investigated. The most effective replacement was found to be the isobutyl group. The cyclopentylmethyl and cyclohexylmethyl groups were also effective benzyl replacements. The cyclohexylmethyl derivative 19 demonstrated the lowest metabolic clearance within this series. In addition, several high affinity substituted benzyl analogues were also identified. Compound 39 was found to have good bioavailability in rats and demonstrated efficacy in the established FCA preclinical model of inflammatory pain with a calculated ED50 of 9.2mg/kg.
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PMID:Structure-activity relationships of 1,5-biaryl pyrroles as EP1 receptor antagonists. 1669 96

Glutamate is the main excitatory neurotransmitter in central nervous system (CNS) and NMDA receptors are one of the major classes of ionotropic glutamate receptors. NMDA receptors have been known to play critical roles in normal CNS activities, as well as in many pathological conditions, including both acute and chronic diseases. The discovery of glycine as a coagonist of NMDA receptors has led to intensive research of glycine/NMDA antagonists as potential CNS drugs. The robust efficacy of glycine/NMDA antagonists, such as ACEA-1021 (5), in animal model of brain ischemia, together with good safety profile in animal models and in clinical trials, suggested that this class of NMDA antagonists should have good chance of success in the clinic as neuroprotectants. The clinical trial of ACEA-1021 for stroke was discontinued, mainly due to low solubility and lack of metabolism of the drug that led to the observation of crystals in the urine of some of the patients. However, through SAR studies, compounds such as ACEA-1416 (10) have been identified with improved properties, such as higher in vivo potency and site for potential metabolism. Therefore these compounds should be able to overcome some of the liabilities of ACEA-1021 and potentially could be developed as neuroprotectants. Based on the preclinical and clinical studies of glycine/NMDA antagonists, as well as the clinical experiences with t-PA, initiation of treatment within a short time window after the onset of stroke could be critical for the success of these antagonists in clinical trials. This can be accomplished by implementing the procedure developed for t-PA clinical trials, with modification based on the safety profile of glycine/NMDA antagonists, for future clinical trial to administer the drug as soon as possible after stroke onset. In addition, glycine/NMDA antagonists also have other potential therapeutic applications, such as for the treatment of traumatic brain injury, pain, cocaine overdose and convulsions.
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PMID:Glycine/NMDA receptor antagonists as potential CNS therapeutic agents: ACEA-1021 and related compounds. 1671 7

We have discovered a novel, potent, and selective triazafluorenone series of metabotropic glutamate receptor 1 (mGluR1) antagonists with efficacy in various rat pain models. Pharmacokinetic and pharmacodynamic profiles of these triazafluorenone analogs revealed that brain/plasma ratios of these mGluR1 antagonists were important to achieve efficacy in neuropathic pain models. This correlation could be used to guide our in vivo SAR (structure-activity relationship) modification. For example, compound 4a has a brain/plasma ratio of 0.34, demonstrating only moderate efficacy in neuropathic pain models. On the other hand, antagonist 4b with a brain/plasma ratio of 2.70 was fully efficacious in neuropathic pain models.
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PMID:Correlation between brain/plasma ratios and efficacy in neuropathic pain models of selective metabotropic glutamate receptor 1 antagonists. 1680 35


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