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1.
Article in English | MEDLINE | ID: mdl-22254697

ABSTRACT

The design, fabrication, and measurement results for a diaphragm-based single crystal silicon sensor element of size 820 µm × 820 µm × 500 µm are presented. The sensor element is designed for in vivo applications with respect to size and measurement range. Moreover, it is optimized for longtime operation in the human body through a built-in protection preventing biofouling on the piezoresistors. The sensitivity is about 20 mV/V for a change from 500 to 1500 mbar absolute pressure. This result is comparable to conventional sized micromachined pressure sensors. The output signal is not found to be influenced by exposure to 60 °C for three hours, a normal temperature load for a typical sterilization process for medical devices (Ethylene Oxide Sterilization). The hysteresis is low; < 0.25% of full scale output signal. The sensor element withstands an overload pressure of 3000 mbar absolute pressure. Observed decrease in the output signal with temperatures and observed nonlinearity can easily be handled by traditional electronic compensation techniques.


Subject(s)
Biofouling/prevention & control , Biosensing Techniques/instrumentation , Micro-Electrical-Mechanical Systems/instrumentation , Prostheses and Implants/microbiology , Transducers, Pressure/microbiology , Equipment Design , Equipment Failure Analysis , Reproducibility of Results , Sensitivity and Specificity
2.
Bioorg Med Chem Lett ; 10(21): 2411-5, 2000 Nov 06.
Article in English | MEDLINE | ID: mdl-11078190

ABSTRACT

The stereoselective synthesis and biological activity of NPS 1407 (4a), (S)-(-)-3-amino-1,1-bis(3-fluorophenyl)butane, a potent, stereoselective antagonist of the NMDA receptor, are described. The racemate (4) was found to be active at the NMDA receptor in an in vitro assay, prompting the synthesis of the individual stereoisomers. The S isomer (4a) was found to be 12 times more potent than the R isomer (4b). Compound 4a demonstrated in vivo pharmacological activity in neuroprotection and anticonvulsant assays.


Subject(s)
Excitatory Amino Acid Antagonists/chemical synthesis , Excitatory Amino Acid Antagonists/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Anticonvulsants/metabolism , Anticonvulsants/pharmacology , Cerebellum/cytology , Cerebellum/drug effects , Dizocilpine Maleate/pharmacology , Excitatory Amino Acid Antagonists/chemistry , Excitatory Amino Acid Antagonists/metabolism , Ischemic Attack, Transient/drug therapy , Mice , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Neuroprotective Agents/metabolism , Neuroprotective Agents/pharmacology , Rats , Receptors, N-Methyl-D-Aspartate/metabolism , Seizures/drug therapy , Stereoisomerism
3.
Amino Acids ; 19(1): 177-9, 2000.
Article in English | MEDLINE | ID: mdl-11026487

ABSTRACT

NPS Pharmaceuticals, Inc. (NPS) has synthesized a series of open-channel blockers with varying potencies at the NMDA receptor. NPS 1506 (Fig. 1) is a moderate affinity antagonist that inhibits NMDA/glycine-induced increases in cytosolic calcium in cultured rat cerebellar granule cells (IC50 = 476nM) and displaces the binding of [3H]MK-801 to rat cortical membranes (IC50 = 664nM).


Subject(s)
Excitatory Amino Acid Antagonists/pharmacology , Fluorobenzenes/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Adolescent , Adult , Animals , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Dizocilpine Maleate/metabolism , Double-Blind Method , Excitatory Amino Acid Antagonists/adverse effects , Excitatory Amino Acid Antagonists/pharmacokinetics , Excitatory Amino Acid Antagonists/therapeutic use , Female , Fluorobenzenes/adverse effects , Fluorobenzenes/pharmacokinetics , Fluorobenzenes/therapeutic use , Humans , Male , Placebos , Rats
4.
Bioorg Med Chem Lett ; 9(14): 1915-20, 1999 Jul 19.
Article in English | MEDLINE | ID: mdl-10450953

ABSTRACT

The synthesis, biological activity, and single crystal X-ray structure of NPS 1392, (R)-(-)-3,3-bis(3-fluorophenyl)-2-methylpropan-1-amine (3a), a potent, stereoselective antagonist of the NMDA receptor, are described. The NMDA receptor selectively bound the levo isomer (3a) over its enantiomer (3b), which prompted a rigorous absolute configuration assignment. NPS 1392 has the R configuration based on the single-crystal X-ray diffraction analysis of the hydroiodide salt of NPS 1392. This compound is a potential neuroprotective agent for use in the treatment of ischemic stroke.


Subject(s)
Propane/analogs & derivatives , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Crystallography, X-Ray , Dizocilpine Maleate/pharmacology , Drug Evaluation, Preclinical , Excitatory Amino Acid Antagonists/pharmacology , Ischemia/drug therapy , Models, Molecular , Neuroprotective Agents/pharmacology , Propane/chemical synthesis , Propane/chemistry , Propane/pharmacology , Rats
5.
Ann N Y Acad Sci ; 890: 450-7, 1999.
Article in English | MEDLINE | ID: mdl-10668449

ABSTRACT

NPS 1506 is a moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. NPS 1506 is neuroprotective in rodent models of ischemic stroke, hemorrhagic stroke, and head trauma, with a 2-hr window of opportunity. Neuroprotectant doses of NPS 1506 ranged from approximately 0.1-1.0 mg/kg, with peak plasma concentrations ranging from 8-80 ng/mL. Even at doses producing behavioral toxicity, NPS 1506 did not elicit MK-801-like behaviors, did not generalize to phencyclidine (PCP), and did not elicit neuronal vacuolization. In a Phase I study, intravenous (i.v.) doses of NPS 1506 from 5-100 mg were well tolerated and provided plasma concentrations in excess of those required for neuroprotection in rodents. Adverse events at the 100-mg dose included mild dizziness and lightheadedness, and mild to moderate ataxia. Neither PCP-like psychotomimetic effects nor cardiovascular effects were noted. The long plasma half-life of NPS 1506 (approximately 60 hr) suggests that a single i.v. dose will provide prolonged neuroprotection in humans.


Subject(s)
Fluorobenzenes/pharmacology , Learning/drug effects , Neuroprotective Agents/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Adolescent , Adult , Animals , Brain Ischemia/drug therapy , Clinical Trials as Topic , Drug Evaluation, Preclinical , Fluorobenzenes/blood , Fluorobenzenes/therapeutic use , Humans , Male , Neuroprotective Agents/blood , Neuroprotective Agents/therapeutic use , Propylamines/pharmacology , Stroke/drug therapy
6.
Pharm Res ; 15(1): 31-8, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9487543

ABSTRACT

PURPOSE: Twelve synthetic spider toxin analogs were prepared in an effort to better understand the structure-activity relationships of the polyamine portion of argiotoxin-636 (Arg-636), a noncompetitive NMDA receptor (NMDAR) antagonist. METHODS: The 1,13-diamino-4,8-diazatridecane portion of the side chain of Arg-636 was systematically modified in an effort to further our knowledge of the structural requirements for the alkyl linker spacing between the amine nitrogens. Systematic isosteric replacement of each of the amine nitrogens in the polyamine moiety with either oxygen or carbon provided a series of compounds which were evaluated in vitro for NMDAR antagonist activity. RESULTS: One-half of the heteroatoms found in Arg-636 were removed to provide analogs which maintained in vitro potency below 1 microM. However, these simplified analogs produced similar or more pronounced effects on the cardiovascular system than Arg-636 in vivo. CONCLUSIONS: In this set of analogs, a minimum of three basic nitrogens in the side chain was required for maximum potency as NMDAR antagonists. Isosteric nitrogen substitutions in the polyamine chain reduced the in vitro potency of these analogs. An analog binding-conformation model was proposed to rationalize the inactivity of these isosterically substituted analogs.


Subject(s)
Blood Pressure/drug effects , Drug Design , Heart Rate/drug effects , Phenylacetates/chemical synthesis , Phenylacetates/pharmacology , Polyamines/chemical synthesis , Polyamines/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Indoleacetic Acids , Male , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/metabolism , Spider Venoms , Spiders
7.
J Med Chem ; 37(12): 1886-8, 1994 Jun 10.
Article in English | MEDLINE | ID: mdl-8021929

ABSTRACT

Indolomorphinans 2 and 3, in which the indole moiety is fused to the 7,8-position of the morphinan system, have been synthesized from dihydropseudocodeinone 4 and evaluated for antagonist activity on the mouse vas deferens (MVD) and guinea pig ileum (GPI) preparations. Indolomorphinan 2 was found to be approximately 1/60th as potent as naltrindole 1 in the MVD and an agonist in the GPI preparation. A comparable difference in affinity between 1 and 2 was observed. The methyl analogue 3 was inactive in both preparations. The results of this study support the idea that the regio orientation of the indolic benzene moiety of 1 is optimal for delta-opioid receptor antagonist activity. It is proposed that the proper alignment of the benzene moiety with an address subsite on the delta receptor is critical for potent delta antagonist activity.


Subject(s)
Indoles/chemical synthesis , Naltrexone/analogs & derivatives , Narcotic Antagonists/chemical synthesis , Receptors, Opioid, delta/antagonists & inhibitors , Animals , Guinea Pigs , In Vitro Techniques , Indoles/chemistry , Indoles/pharmacology , Isomerism , Mice , Naltrexone/chemical synthesis , Naltrexone/chemistry , Naltrexone/pharmacology , Narcotic Antagonists/chemistry , Narcotic Antagonists/pharmacology
8.
J Med Chem ; 37(5): 579-85, 1994 Mar 04.
Article in English | MEDLINE | ID: mdl-8126697

ABSTRACT

Naltrindole (1) (NTI) is a highly potent and selective delta-opioid receptor antagonist. In an effort to understand the origin of the high potency, affinity, and selectivity of NTI, we have examined the conformational role of its indolic benzene moiety through the synthesis of related naltrexone derivatives 3-8, which contain the benzene moiety in different orientations and at different attachments in the molecule. One of these naltrexone derivatives, 5, whose 7-indanyl benzene moiety is orthogonal to ring C of the morphinan system, is a potent delta-opioid receptor antagonist in vitro and in vivo. Computer-assisted molecular overlay studies of the minimized structures (2-8) revealed the importance of the position of the benzene moiety for effective interaction with delta-opioid receptors. In compounds 2, 4, and 5, the aromatic ring falls in the same region of space as that of the indolic benzene moiety of NTI, and all of these ligands possessed significant activity at delta-opioid receptors. Analogues (3 and 6-8) which were shown to have relatively weak delta-opioid receptor antagonist potency have their aromatic groups located in a space that is different from that of the more potent analogues.


Subject(s)
Naltrexone/analogs & derivatives , Receptors, Opioid, delta/antagonists & inhibitors , Animals , Benzylidene Compounds/chemical synthesis , Benzylidene Compounds/metabolism , Benzylidene Compounds/pharmacology , Electric Stimulation , Guinea Pigs , Ileum/physiology , Male , Mice , Models, Molecular , Molecular Conformation , Molecular Structure , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Naltrexone/chemical synthesis , Naltrexone/chemistry , Naltrexone/metabolism , Naltrexone/pharmacology , Receptors, Opioid, delta/metabolism , Structure-Activity Relationship , Vas Deferens/physiology
9.
J Biol Chem ; 268(31): 23055-8, 1993 Nov 05.
Article in English | MEDLINE | ID: mdl-8226821

ABSTRACT

The enkephalins, dynorphins, and endorphins are endogenous opioids which function as neurotransmitters, neuromodulators, and hormones and are involved in the perception of pain, modulation of behavior, and regulation of autonomic and neuroendocrine function. Pharmacological studies have defined three classes of opioid receptors, designated as delta, kappa, and mu. To investigate mechanisms by which agonists and antagonists interact with the delta opioid receptor, we have substituted aspartic acid 95 in the transmembrane segment 2 of the cloned mouse delta opioid receptor with an asparagine (D95N). The D95N mutant receptor had reduced affinity for delta receptor-selective agonists such as enkephalin, [D-Pen2,D-Pen5]enkephalin and [D-Ser2,Leu5]enkephalin-Thr6 such that it did not bind these peptides even at micromolar concentrations. The binding of delta-selective non-peptide agonists was also reduced. In contrast, the delta receptor-selective antagonists, such as naltrindole, the benzofuran analog of naltrindole, and 7-benyllidenenaltrexone, bound equally well to the wild-type and mutant receptor. Similarly, non-selective opioid agonists such as bremazocine and buprenorphine, which interact with delta, kappa, and mu opioid receptors, showed no difference in binding to the wild-type and mutant delta receptor. The D95N mutant remained coupled to G proteins, and the receptor was functionally active since it mediated agonist inhibition of cAMP accumulation. These results indicate that selective agonists and antagonists bind differently to the delta receptor and show that Asp-95 contributes to high affinity delta-selective agonist binding. The identification of a key residue involved in selective agonist binding to the delta opioid receptor will facilitate the development of novel therapeutic reagents that can be used for the treatment of chronic pain and other conditions.


Subject(s)
Receptors, Opioid, delta/chemistry , Animals , Aspartic Acid/chemistry , Base Sequence , Binding Sites , Binding, Competitive , Cell Line , Chlorocebus aethiops , Colforsin/pharmacology , Cyclic AMP/biosynthesis , Enkephalins/metabolism , Guanosine Triphosphate/pharmacology , In Vitro Techniques , Mice , Molecular Sequence Data , Mutagenesis, Site-Directed , Narcotics/metabolism , Oligodeoxyribonucleotides/chemistry , Protein Binding , Receptors, Opioid, delta/metabolism , Recombinant Proteins , Signal Transduction , Sodium/pharmacology , Structure-Activity Relationship
11.
J Med Chem ; 36(10): 1316-8, 1993 May 14.
Article in English | MEDLINE | ID: mdl-8098770

ABSTRACT

The subject compounds were prepared as a part of a continuing structure-activity study of the contrasting actions (agonism-antagonism) of (+)- and (-)-11-hydroxy-10-methylaporphine at serotonin (5-HT1A) receptors. None of the targeted nonoxygenated aporphine derivatives demonstrated significant activity in assays for any effects at serotonin 5-HT1A receptors. It is concluded that, in the aporphine series, serotonergic agonist or antagonism requires an alkyl group ortho to a phenolic OH group in the A ring.


Subject(s)
Aporphines/chemical synthesis , Dopamine Agents/chemical synthesis , Animals , Aporphines/chemistry , Aporphines/pharmacology , Dopamine Agents/pharmacology , Guinea Pigs , Hemodynamics/drug effects , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Rats , Receptors, Dopamine/drug effects , Receptors, Serotonin/drug effects , Stereoisomerism , Structure-Activity Relationship
12.
Chirality ; 3(1): 19-23, 1991.
Article in English | MEDLINE | ID: mdl-2039679

ABSTRACT

The two enantiomers of the title compound have been prepared by different synthetic routes. Both bind strongly to 5-HT1A receptors from rat forebrain membrane tissue. However, in a guinea pig ileum preparation, the (R)-enantiomer exhibits properties consistent with its being an agonist, whereas the (S)-enantiomer shows no agonist effect, but it blocks the actions of the (R)-enantiomer and of 8-hydroxy-2-di-n-propylaminotetralin (8-OH-DPAT), a 5-HT1A agonist. These data are presented as a rare example of enantiomers which demonstrate opposite pharmacological effects at the same receptor.


Subject(s)
Aporphines/pharmacology , Cerebral Cortex/metabolism , Muscle Contraction/drug effects , Receptors, Serotonin/metabolism , Animals , Aporphines/chemical synthesis , Aporphines/metabolism , Cell Membrane/metabolism , Guinea Pigs , Ileum/drug effects , Ileum/physiology , In Vitro Techniques , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Rats , Receptors, Serotonin/drug effects , Stereoisomerism , Structure-Activity Relationship
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