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Biomedical subjects

D M Zimmerman

Publications and source records attributed to D M Zimmerman.

48 records · Page 3Linked to original sources
PubMed1985

Picenadol.

Picenadol is a unique opioid mixed agonist-antagonist analgesic currently under clinical evaluation. Structurally, picenadol is a 4-phenylpiperidine derivative and a racemic mixture whose mixed agonist-antagonist properties are a consequence of the d-isomer being a potent opiate agonist, whereas the l-isomer is an opioid antagonist. In the mouse writhing and rat tail heat tests, the analgesic potency of picenadol is estimated to be 1/3 that of morphine. Picenadol itself has weak antagonist activity, whereas the antagonist potency of the l-isomer is approx. 1/10 that of nalorphine. Evaluation of picenadol's affinity for opioid receptors reveals that picenadol, unlike other mixed agonist-antagonists has high affinity for both the mu and delta receptors but a markedly lower affinity for the kappa receptor. Extensive pharmacological investigations show picenadol to have a low potential to produce opiate-like side effects, including a low liability for abuse and physical dependence.

Animals↗
PubMed1984

Phencyclidine receptors in rat brain cortex.

The binding of [3H]phencyclidine (PCP) to receptors in rat brain cortex has been studied. Two receptors have been detected, a high affinity receptor site with a KD of 23.5 +/- 7.4 nM and a low affinity site with a KD of 7.6 +/- 1.8 microM. The binding of [3H]PCP to its receptors was pH and temperature dependent and was destroyed by heat-denaturation. The binding of [3H]PCP was inhibited by compounds which produce PCP-like behavioral effects including dexoxadrol, etoxadrol and ketamine as well as a novel series of benz(f)isoquinolines. The low affinity site was blocked by PCP, etoxadrol and (+)-SKF-10,047 but not morphine or leu-enkephalin, suggesting that it also represents a specific PCP site. Stereoselective displacement of PCP at the high affinity receptor was observed with the isomers of cyclazocine, cyclorphan, SKF-10,047 and dioxadrol (dexoxadrol and levoxadrol). Naloxone, 4,5,6,7-tetrahydroisoxazolo(S,4-C)pyridin-3-ol (THIP) hydrate and haloperidol inhibited binding poorly (Ki greater than 1 microM), suggesting that these compounds do not interact significantly with the high affinity PCP receptor in vivo. The affinity of ligands for the phencyclidine receptor was highly correlated (r = 0.714, P less than 0.01) with their potency to produce catalepsy in pigeons.

Animals↗
PubMed1983

Effects of picenadol and its agonist and antagonist isomers on schedule-controlled behavior.

The effects of picenadol and its (+)- and (-)-isomers were determined on the responding of pigeons under a multiple fixed-ratio (FR) 50-response, fixed-interval (FI) 5-min schedule of grain presentation. Picenadol decreased responding in both schedule components as a function of dose (0.64-10 mg/kg). Naloxone shifted to the right the picenadol dose-effect curve in the FR component (2.8-fold), but had little effect on the dose-effect curve for FI responding. Similarly, the (+)-isomer decreased responding in both schedule components, but naloxone was only able to shift to the right the dose-effect curve for the (+)-isomer on FR responding (2-fold). The effects of the (+)-isomer on FI responding were not affected by naloxone. The (-)-isomer decreased responding at high doses (20 and 40 mg/kg) and this effect was not antagonized by naloxone. The dose-effect curves for the (-)-isomer were shifted markedly to the left in animals maintained on daily doses (30 or 60 mg/kg p.o.) of methadone. Low doses (2.5-20 mg/kg) of the (-)-isomer antagonized the behavioral suppressant effects of 5 mg/kg of l-methadone. The (+)-isomer, but not the (-)-isomer, antagonized the complete behavioral suppression produced by 0.05 mg/kg of oxotremorine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Novel phenylpiperidine opioid antagonists and partial agonists: effects on fluid consumption.

The effects of five opioid antagonists, a racemate partial agonist and its agonist and antagonist optical isomers were studied on deprivation-induced drinking. All compounds had a phenylpiperidine nucleus. The antagonists produced dose-related decreases in drinking, and the potencies for decreasing drinking correlated with morphine-antagonist doses. The racemic partial agonist and its agonist isomer decreased drinking at doses higher than those which produced marked analgesia. Within the class of phenylpiperidine drugs studied, some had less specificity than naloxone for the mu-receptors as compared to the delta-receptor, but the suppression of drinking was not related to changes in mu-to-delta ratios.

Animals↗
PubMed1979

Onset of neural function in the lateral line.

The development of the nervous system includes the formation of specific neuronal connections. Some insight into the mechanisms by which these connections are made may be obtained by determining the order in which the elements of a developing system begin to function and examining any changes that may occur in the system shortly after it begins functioning. I have investigated the lateral line of the South African clawed frog, Xenopus laevis and I have classified the afferent system into three elements. First, the transduction mechanism, which includes all components that couple the water vibrations to the release of transmitter from the hair cell. Second, the afferent synapse, at which there is transmitter release and subsequent postsynaptic conductance changes. And third, the afferent axon. I report here experiments suggesting that these elements become functional in the following order: first, the axon can conduct action potentials; second, transmission is established; third, the transduction mechanism can modulate transmitter release. This same sequence has been reported in a system related to the lateral line, the auditory pathway of mammals.

Afferent Pathways↗
PubMed1979

Asymptomatic glomerulonephritis after nonstreptococcal upper respiratory infections.

Two hundred forty previously healthy military personnel with nonstreptococcal upper respiratory infections were prospectively studied to define the incidence and clinicopathologic characteristics of possible virus-associated glomerulonephritis. Nine patients without preceding streptococcal infection had erythrocyte casts on urinalysis and glomerulonephritis on biopsy. Of these nine, four had a reduction in total hemolytic complement and five had serologic evidence of infection with adenovirus, influenza A, or influenza B. Initial renal biopsy showed either focal or diffuse mesangial proliferation in all nine, with mesangial C3 deposits in six specimens. Repeat biopsy in three showed histologic improvement or loss of immunofluorescent staining, or both. Sequential creatinine clearances were reduced to 74 to 90 mL/min.1.73 m2 in five patients for the duration of follow-up. We conclude that nonstreptococcal upper respiratory infection is frequently associated with glomerulonephritis and that abnormal glomerular structure and decreased creatinine clearances may persist for at least 2 to 8 months.

Adenoviridae Infections↗
PubMedDate not supplied

Phenylpiperidine opioid antagonists that promote weight loss in rats have high affinity for the kappa 2B (enkephalin-sensitive) binding site.

Certain opioid antagonists of the phenylpiperidine series (PPAs), such as LY255582, seem uniquely efficacious at producing weight loss in lean and meal-fed obese Zucker rats. Comparison of the pharmacological and receptor binding profile of PPAs that promote marked weight loss with those that do not has failed to find any obvious differences between these two groups of narcotic antagonists, which might explain the differences in their biological activities. The potent stimulatory effect of dynorphin, and other kappa agonists, on feeding behavior suggests that the antagonists that promote weight loss might have high affinity for kappa receptors. The recent demonstration by several laboratories of kappa receptor heterogeneity prompted us to test the hypothesis that the antagonists that promote weight loss might have high affinity for a subtype of kappa binding sites. In the present study, therefore, we determined the Ki values of five PPAs, naloxone, and naltrexone at mu, delta, kappa 1, kappa 2a, and kappa 2b binding sites. The data indicate that antagonists have subnanomolar Ki values and high selectivity for the kappa 2b binding site (relative to the kappa 2a binding site) are efficacious at promoting weight loss.

Animals↗
PubMedDate not supplied

Immunohistochemical evaluation of chemically induced rhabdomyosarcomas in rats: diagnostic utility of MyoD1.

Monoclonal antibodies (mAbs) to selected muscle proteins were assessed as potential immunohistochemical markers to assist in the definitive diagnosis of poorly differentiated soft tissue sarcomas in rats. A series of 7 rat rhabdomyosarcomas (RMS) induced with nickel subsulfide were studied by light microscopy and were evaluated for immunoreactivity to desmin, vimentin, fast (type II isoform) skeletal myosin, alpha-actin (smooth muscle isoform), or MyoD1 (myogenic regulatory protein) mAbs using an avidin-biotin-chromogen technique. Consecutive RMS slices were fixed in 10% neutral buffered formalin (the fixative routinely used in carcinogenicity bioassays) for periods of 3 days or 2 mo prior to paraffin embedding to determine the effect of fixation time on immunoreactivity. Desmin and vimentin mAbs bound to many cells of all tumors, but fixation for 2 mo resulted in irretrievable loss of desmin and vimentin binding. Fast myosin and alpha-actin mAbs bound to many cells in 1 RMS but to < 1% of the cells in the remainder. MyoD1 mAb bound to tumor cell nuclei in 5/7 RMS with no loss of staining in tissue fixed for 2 mo. Results indicate that MyoD1 immunostaining, in contrast to desmin, maintains its sensitivity following prolonged formalin fixation and may be of value to distinguish RMS from other soft tissue sarcomas in the rat.

Animals↗