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Dive into the research topics where Philip F. VonVoigtlander is active.

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Featured researches published by Philip F. VonVoigtlander.


Life Sciences | 1982

Properties of a selective kappa agonist, U-50,488H

Robert A. Lahti; Philip F. VonVoigtlander; Craig L. Barsuhn

U-50,488H has been shown to be a naloxone antagonizable analgesic in rodents. However, the dose of naloxone needed for antagonism is higher than it is for morphine. U-50,488H does not produce physical dependence; however it does produce tolerance upon chronic administration. U-50,488H is cross tolerant with bremazocine but not with morphine. Monkeys trained to discriminate ethylketocyclazocine (EKC) from saline show a complete generalization to U-50,488H but not to morphine. The evaluation of U-50,488H in 3H-EKC site-selective binding indicated that U-50,488H has a high affinity for the kappa receptor (Ki = 114 nM) and a low affinity for the mu receptor (Ki = 6100 nM). The ratio of Ku/Kk was 0.08 for morphine, 0.4 for dynorphin, and 53.5 for U-50,488H. The data suggest that U-50,488H is a selective agonist at the opioid kappa receptor.


Molecular and Chemical Neuropathology | 1993

The use of salicylate hydroxylation to detect hydroxyl radical generation in ischemic and traumatic brain injury : reversal by tirilazad mesylate (U-74006F)

John S. Althaus; Paula K. Andrus; Philip F. VonVoigtlander; Alexander R. Cazers; Edward D. Hall

Oxygen free radicals have been implicated as a causal factor in posttraumatic neuronal cell loss following cerebral ischemia and head injury. The conversion of salicylate to dihydroxybenzoic acid (DHBA) in vivo was employed to study the formation of hydroxyl radical (.OH) following central nervous system (CNS) injury. Bilateral carotid occlusion (BCO) in gerbils and concussive head trauma in mice were selected as models of brain injury. The lipid peroxidation inhibitor, tirilazad mesylate (U-74006F), was tested for its ability to attenuate hydroxyl radical formation in these models. In addition, U-74006F was studied as a scavenger of hydroxyl radical in an in vitro assay based on the Fenton reaction. For in vivo experimentation, hydroxyl radical formation was expressed as the ratio of DHBA to salicylate (DHBA/SAL) measured in brain. In the BCO model, hydroxyl radical formation increased in whole brain with 10 min of occlusion followed by 1 min of reperfusion. DHBA/SAL was also found to increase in the mouse head injury model at 1 h postinjury. In both models, U-74006F (1 or 10 mg/kg) blocked the increase in DHBA/SAL following injury. In vitro, reaction of U-74006F with hydroxyl radical gave a product with a mol wt that was 16 greater than U-74006F, indicative of hydroxyl radical scavenging. We speculate that U-74006F may function by blocking oxyradical-dependent cell damage, and thereby maintaining free iron (which catalyzes hydroxyl radical formation) concentrations at normal levels.


Journal of Medicinal Chemistry | 1996

3-Phenyl-Substituted Imidazo[1,5-a]quinoxalin-4-ones and Imidazo[1,5-a]quinoxaline Ureas That Have High Affinity at the GABAA/Benzodiazepine Receptor Complex†

E. J. Jacobsen; L. S. Stelzer; K. L. Belonga; Donald B. Carter; Wha Bin Im; Vimala H. Sethy; Andrew H. Tang; Philip F. VonVoigtlander; J. D. Petke

A series of imidazo[1,5-alpha]quinoxalin-4-ones and imidazo[1,5-alpha]quinoxaline ureas containing substituted phenyl groups at the 3-position was developed. Compounds within the imidazo[1,5-alpha]quinoxaline urea series had high affinity for the GABAA/benzodiazepine receptor complex with varying in vitro efficacy, although most analogs were partial agonists as indicated by [35S]TBPS and Cl- current ratios. Interestingly, a subseries of piperazine ureas was identified which had biphasic efficacy, becoming more antagonistic with increasing concentration. Analogs within the imidazo[1,5-alpha]quinoxalin-4-one series had substantially decreased binding affinity as compared to the quinoxaline urea series. These compounds ranged from antagonists to full agonists by in vitro analysis, with several derivatives having roughly 4-fold greater intrinsic activity than diazepam as indicated by Cl- current measurement. Numerous compounds from both series were effective in antagonizing metrazole-induced seizures, consistent with anti-convulsant properties and possible anxiolytic activity. Most of the quinoxaline ureas and quinoxalin-4-ones were active in an acute electroshock physical dependence side effect assay in mice precluding further development.


Journal of Pharmacological Methods | 1991

A rapid screening method for the assessment of benzodiazepine receptor-related physical dependence in mice: Evaluation of benzodiazepine-related agonists and partial agonists

Philip F. VonVoigtlander; Richard A. Lewis

We have developed a model of benzodiazepine-type physical dependence in which mice were injected subcutaneously with the test compound on a fixed schedule (0800 and 1600 for 3 days, the PM dose = AM dose x 2). If tolerated, then a starting dose of 150 mg/kg/day was generally used initially and the dose was lowered to 15 and 1.5 mg/kg/day in subsequent assays if the higher doses were active in the test. Twenty-four hours after the last dose, the mice received an intravenous injection of flumazenil (2.5 mg/kg), and 5 min later they were tested for electroshock seizure thresholds by an up-down titration method. Flumazenil-precipitated withdrawal was manifested by a lowering of the mA seizure threshold. We have found that compounds with benzodiazepine agonist properties significantly lower these thresholds in a dose-related fashion. For example, the following compounds (lowest effective mg/kg/day dose) were active in this regard, chlordiazepoxide (150), diazepam (15), flurazepam (15), alprazolam (15), triazolam (15), midazolam (15), zopiclone (150), Ro 16-6028 (150), and Ro 17-1812 (150). In contrast, zolpidem (150), tracazolate (15), and CL 218872 (15) did not cause physical dependence by this criterion. This rapid and simple screening test may be readily used to predict the physical-dependence-inducing properties of compounds that act at the benzodiazepine receptor.


Progress in Neuro-psychopharmacology & Biological Psychiatry | 1983

Involvement of biogenic amines with the mechanisms of novel analgesics

Philip F. VonVoigtlander; Richard A. Lewis; Gary L. Neff; Herman J. Triezenberg

The analgesic activity of the kappa opioid agonist, U-50,488H, was markedly antagonized by pretreatment with reserpine, p-chlorophenylalanine, and ketanserin. Likewise, analgesic doses of U-50,488H enhance serotonin metabolism. These results suggest that kappa analgesia requires serotonin acting through 5-HT2 receptors. The non-opioid analgesic, nefopam HCl, though a blocker of biogenic amine uptake, displays an analgesic spectrum of action more similar to that of amphetamine than that of the tricyclic antidepressants or serotonin uptake blockers. Likewise p-chlorophenylalanine and ketanserin do not block nefopam analgesia nor do naloxone, atropine, yohimbine, propranolol or haloperidol. However, as reserpine does block nefopam analgesia, biogenic amines acting at other receptors may be involved. The observation that m-tyrosine causes behavioral effects similar to high doses of nefopam suggested that they might be acting through similar mechanisms. However, although m-tyrosine causes analgesia, it is blocked by yohimbine. This suggests that alpha2-adrenoreceptors are involved in m-tyrosine analgesia and that it differs in mechanism from nefopam analgesia.


Free Radical Biology and Medicine | 1997

EFFECTS OF LAZAROIDS AND A PEROXYNITRITE SCAVENGER IN A CELL MODEL OF PEROXYNITRITE TOXICITY

G.J. Fici; John S. Althaus; Philip F. VonVoigtlander

We developed a cerebellar granule cell model of peroxynitrite toxicity and showed that certain sulfhydryl-containing compounds (e.g., penicillamine) present as concurrent treatments could inhibit this toxicity. In the present study, 21-aminosteroid and pyrrolopyrimidine lazaroids were tested for cytoprotection in this peroxynitrite toxicity model. In addition, we tested for added protection using a peroxynitrite scavenger concurrent treatment combined with a lazaroid post-treatment. The toxicity assay utilized cells that were previously exposed to 100 microM L-buthionine (S,R)-sulfoximine (BSO), an inhibitor of gamma-glutamyl-cysteine synthetase, for 24 h. This sublethal concentration of BSO shifted the peroxynitrite (1-1000 microM) toxicity curve to the left by more than one-half of a log unit. The half-maximal toxicity concentration (TC50) of peroxynitrite in cells treated with BSO was 50 microM. The 21-aminosteroids, U-74006F and U-74500A, and the pyrrolopyrimidines, U-91736B and U-101033E, were tested as post-treatments. U-74006F and U-74500A had EC50 values of approximately 100 microM (concentrations which blocked 50% of the toxicity). U-91736B and U-101033E had EC50 values of 1 microM and showed 100% protection at 3-10 microM. Treatment with either 100 microM U-74006F or 1 microM U-101033E resulted in a right-hand shift (protection) in the peroxynitrite toxicity curve. Further, combination treatment of lazaroids with 1 mM penicillamine resulted in additive protection compared to either treatment alone.


European Journal of Pharmacology | 1996

Pharmacology of U-91356A, an agonist for the dopamine D2 receptor subtype

Montford F. Piercey; Malcolm W. Moon; Vimala H. Sethy; Peggy J. K. D. Schreur; Martin W. Smith; Andrew H. Tang; Philip F. VonVoigtlander

U-91356A [(R)-5,6-dihydro-5-(propylamino)4H-imidazo[4,5,1-ij]quinolin -2-(1H)-one, monohydrochloride], bound with highest affinity to the dopamine D2 receptor subtype, although it also bound with somewhat lower affinities to the dopamine D3 and D4, as well as the 5-HT1A receptor subtypes. In addition to depressing dopamine synthesis and turnover, injection of U-91356A increased striatal acetylcholine concentrations. U-91356A also depressed firing rates of dopamine neurons. In mice, this compound stimulated cage climbing and locomotor activity in reserpinized animals; it also antagonized D-amphetamine-stimulated locomotor activity. It produced contralateral turning in rats with unilateral lesions of the substantia nigra. These data are consistent with roles for the dopamine D2 receptor subtype as a dopamine autoreceptor and as a stimulatory, postsynaptic dopamine receptor.


British Journal of Pharmacology | 1992

Comparison of pyrrolidinyl and piperidinyl benzamides for their anticonvulsant activity and inhibitory action on sodium channel

Yu Zhu; Wha Bin Im; Richard A. Lewis; Philip F. VonVoigtlander

1 A pair of benzamide analogues containing a pyrrolidinyl or piperidinyl group was examined for their anticonvulsant activity against the electroshock‐induced seizures in mice and the ability to block the voltage‐gated Na channel in N1E‐115 cells, in comparison with the prototype compound, U‐54494A, (±)‐cis‐3,4‐dichloro‐N‐methyl‐N‐[2‐(1‐pyrrolidinyl)‐cyclohexyl]‐benzamide, a potent anticonvulsant and a Na channel blocker. 2 The pyrrolidinyl benzamide (U‐49524E) was found to be effective against the electroshock‐induced seizures (ED50 = 35 mg kg−1, i.p.) whereas the benzamide with a piperidinyl moiety (U‐49132E) was inactive (ED50> 100 mg kg−1). 3 Using whole‐cell patch clamp techniques we found that U‐49132E was several times less potent, with an IC50 of 396 μm as compared to 118 μm for U‐49524E at the holding potential of − 80 mV, and was much slower in blocking Na channels with a half‐time of 10.7 ± 1.1 min vs. 2.2±0.4 min for its counterpart. 4 Qualitatively, their general modes of interaction with Na channels were similar to each other and to that of U‐54494A in that they interacted with the resting and slowly‐inactivated states of the channels and exhibited a use‐dependent inhibition because of a slow recovery from the inactivated state in the presence of the drugs. 5 Comparison of their physicochemical properties, shows the less potent and slowly acting U‐49132E is more hydrophobic and bulkier than U‐49524E, but has the same pKa. This suggests that the drugs approach the Na channel through a narrow and hydrophilic pathway. 6 Overall, this study underscores the importance of inhibiting the Na channel to the anticonvulsant activity of the benzamide compounds.


Journal of Pharmacological Methods | 1983

A withdrawal hyperalgesia test for physical dependence: Evaluation of μ and mixed-partial opioid agonists

Philip F. VonVoigtlander; Richard A. Lewis

The physical dependence-inducing properties of analgesics are commonly assessed by the appearance of typical narcotic withdrawal signs (weight loss, jumping, etc.) upon cessation of administration or treatment with a narcotic antagonist. We sought to develop a simple model of physical dependence based upon withdrawal hyperalgesia. The test compound was injected seven times over a period of three days. At various times after the last injection, 6% aqueous NaCl was injected i.p. and the mice were observed for stereotyped writhing. To assess the magnitude of hyperalgesia, the animals were also challenged with several concentrations of saline administered at the time of peak sensitivity and a saline EC50 was thereby derived. In this manner, it was demonstrated that morphine causes a marked, dose-related physical dependence. Other mixed opioids, pentazocine, ethylketocyclazocine, nalbuphine, and butorphanol (in decreasing order of effectiveness) were also active. In nonpretreated mice, naloxone caused a dose-related appearance of saline-induced writhing, suggestive of a blockade of endogenous analgesic mechanisms. Writhing in response to low concentrations of i.p. saline provides a sensitive test of analgesic physical dependence.


Life Sciences | 1978

6-hydroxydopa depletes both brain epinephrine and norepinephrine: interactions with antidepressants.

Philip F. VonVoigtlander; Elizabeth G. Losey

Abstract Intravenous administration of the neurotoxic agent, 6-hydroxydopa, to mice lowered both epinephrine and norepinephrine concentrations in the brainstem. Pretreatment with the tricyclic antidepressant drugs, imipramine, iprindole, and protriptyline, differentially blocked these depletions. Imipramine and protriptyline blocked both the effects on epinephrine and norepinephrine, although higher doses were required to protect epinephrine. Iprindole selectively blocked epinephrine depletions.

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