2-Azabicyclo (2.2.2)octane analogues of the prodine analgetics.

The synthesis and analgetic activity of analogues of prodine-type analgetics in which the conformation of the piperidine ring is restricted in the boat form using the 2-azabicyclo (2.2.2)octane nucleus are reported. One of these analogues, 2-methyl-6-trans-phenyl-6-cis-propionoxy-2-azabicyclo (2.2.2)octane (3), showed significant analgetic activity (ED50 equals 3.1 mg/kg).

Relationships between opiate receptor binding and analgetic properties of prodine-type compounds.

The receptor binding affinities of some diastereoisomeric prodine analgoues have been compared with their analgetic activities determined by the hot-plate test in mice. The close correlation found between these potencies indicates that the relative analgetic activities of the alpha/beta isomers are determined primarily by the appropriate association to the receptor sites.

Combined analgesic/neuroleptic activity in N-butyrophenone prodine-like compounds.

Some 4-phenyl-4-piperidinols, corresponding esters, and related compounds with a p-fluorobutyrophenone chain on nitrogen were synthesized and evaluated in in vitro and in vivo tests in order to examine their ability to interact contemporaneously with opioid and dopamine receptors. The propionyloxy derivatives showed a good combination of analgesic and neuroleptic activity. With a 3-methyl substituent on the piperidine ring, the beta-configuration was the more active form not only for analgesic activity, as expected from previous results on prodines, but also for neuroleptic activity. Haloperidol and its propionate were also tested as reference compounds.

Common stereospecificity of opioid and dopamine systems for N-butyrophenone prodine-like compounds.

The two optical isomers of 1-[3-(p-fluorobenzoyl) propyl]-3-methyl-4-phenyl-4-propionoxypiperidine (FPP) were obtained by resolution of (+/-)-r-3-methyl-4-phenyl-c-4-piperidinol followed by N-alkylation and O-propionylation. These, as well as the racemate, were evaluated for their antinociceptive, opioid, and neuroleptic properties using in vivo and in vitro test systems. The results are remarkable in two respects, namely, the dextrorotatory isomer is consistently the most potent on all tests, and it acts on both opioid (mu) and neuroleptic (D2) receptors.

The effect of narcotic analgesics on the uptake of 5-hydroxytryptamine and (-)-metaraminol by blood platelets.

1. The effects of narcotic analgesic and related drugs were studied on the uptake of 5-hydroxytryptamine (5-HT) and (-)-metaraminol by blood platelets.2. The most potent drug in inhibiting the uptake of 5-HT (10 muM) by human platelets was methadone, followed by pentazocine>piminodine approximately pethidine approximately anileridine approximately cyclazocine approximately thebaine > dextropropoxyphene. Alphaprodine, papaverine, apomorphine, nalorphine, codeine, and morphine were almost without effect. Methadone was slightly less active than desipramine, and had 10% of the activity of imipramine under similar conditions. Naloxone did not antagonize the effect of methadone on 5-HT uptake.3. The most potent inhibitor of metaraminol (3 muM) uptake by human platelets was piminodine, followed by pentazocine>/=anileridine>cyclazocine=methadone > dextropropoxyphene approximately thebaine >/= papaverine approximately alphaprodine >pethidine>morphine. The activity of morphine was 1% of that of piminodine. Piminodine was more potent than desipramine and protriptyline under similar conditions. The order of potency of drugs studied in inhibiting the uptake of metaraminol by rabbit platelets was similar to that obtained with human platelets.4. The effects of the analgesics studied on inhibiting uptake of monoamines did not correlate with their pain-relieving properties.

The effect of drugs on uterine activity.

Uterine activity was measured for a 30-minute preinjection period and a 30-minute postinjection period for six drugs commonly used in labor. Uterine activity was quantitated by measuring the area below the uterine pressure curve with an on-line technic utilizing a voltage control oscillator. Uterine activity readings were obtained every 2.5 minutes and reported in uterine activity units (UAU). Unmedicated labor demonstrated a relatively static increase in UAU per unit of time in labor. On comparing total UAU before and after injection, only magnesium sulfate was noted to cause a decrease in total UAU. Utilizing 10-minute summations of UAU, the pre- and postinjection periods were compared to the calculated expected UAU for the 30 minutes following the preinjection period (assuming no drug had been used). For each of the other drugs, the positive slope of the calculated expected UAU shifted to a negative slope of the actual observed UAU following drug administration.

Electronic study of receptor binding of analgesic aryl moiety II: Prodine analogs.

Analogs of the prodine analgesics were prepared and tested for analgesic activity. A good correlation seems to exist between the energy level of the highest occupied molecular orbital and biological activity. The energy level of the highest occupied molecular orbital of the aryl moiety of these analogs may permit a charge transfer interaction between the aryl groups of the analgesic molecules and their receptors with the aryl groups acting as charge donors.

Electric shock titration: effects of meperidine, anileridine and alphaprodine.

The effects of meperidine, anileridine and a alphaprodine were studied in the squirrel monkey whose behavior was maintained under a 2.0-sec schedule of shock increment. Low doses of all three drugs had no effect, whereas higher doses decreased responding at the zero shock intensity. Slightly higher doses of meperidine and anileridine increased responding at the zero shock intensity and produced convulsions.

Comparison of morphine, meperidine, anileridine, and alphaprodine on schedule-controlled responding and analgesia.

The effects of morphine, meperidine, alphaprodine, and anileridine were studied alone and in the presence of 1 mg/kg of naloxone in rats on level pressing under a fixed-ratio 20-response schedule of food presentation and on tail-withdrawal latency from warm water (55 degrees C) as a measure of analgesia. All four narcotics decreased rates of lever pressing and increased tail-withdrawal latencies. Naloxone antagonized the effects of all four narcotics on tail-withdrawal, but did not antagonize the rate-decreasing effect of meperidine on lever pressing. Naloxone shifted the morphine dose-effect for lever-pressing by a factor of 4-8; the alphaprodine dose-effect curve by a factor of 4-8; and the anileridine dose-effect curve by a factor of 2. These results strengthen the interpretation that meperidine's effect on schedule-controlled responding is not mediated by a narcotic action whereas the analgesic effect is. The results also suggest that anileridine has significant non-narcotic actions like meperidine.

Maternal and fetal response to alphaprodine during labor. A preliminary study.

Alphaprodine is a synthetic narcotic, structurally similar to meperidine. Respiratory depression has been reported as a not-infrequent side effect when larger doses of alphaprodine were used, particularly intravenously. In this study, the maternal respiratory rate and tissue pO2 and pCO2 were determined in patients receiving alphaprodine, 0.4 mg/kg of prepregnancy weight, for first-stage analgesia. Statistically significant falls in maternal tcpO2 and increases in tcpCO2 were observed. The baseline fetal heart rate decreased significantly 20 minutes after the injection (139 to 132 bpm). There was no increase in abnormal fetal heart rate patterns. The variability of the baseline fetal heart rate was unchanged until 25 minutes following alphaprodine administration, when a significant reduction occurred. The changes seen in the parameters monitored in this study were not associated with any clinically adverse effects on the mother or fetus.

Problems of medication with the pediatric patient.

During the course of dental treatment, when it is necessary to prescribe pharmacologic agents for the pediatric patient, a drug should be selected that is not only effective but also available in a readily acceptable form. Dosages should be considered carefully. Rather than attempting to adjust adult recommendations, established guidelines for children should be utilized. Manufacturer's doses should be followed when available. If a child frustrates efforts toward treatment and does not respond to nonpharmacotherapeutic management approaches, premedication should be considered. The practitioner should have a thorough medical history before deciding to employ outpatient sedation. This history can be helpful in selecting the most appropriate regimen. Very young children and severely compromised patients are not good candidates for sedation and are best treated under general anesthesia. Narcotic analgesics are rarely indicated for control of pain following dental treatment in children. Nonnarcotic preparations are very effective and will suffice for most procedures. Because prolonged bleeding has been demonstrated, aspirin should be used with caution in surgical cases. Oral administration is recommended for most dental infections requiring antibiotics. In instances when severe infection is encountered, the parenteral route is suggested. A narrow-spectrum, bactericidal agent is preferred; barring allergy, penicillin is the usual drug of choice. When antibiotic prophylaxis is indicated, adherence to American Heart Association guidelines is strongly encouraged.

Risk appraisal of narcotic sedation for children.

Since the use of narcotics was initially advocated 28 years ago, serious adverse reactions, including fatalities, have been reported. At least four factors appear to contribute to these reactions: multiple drug administration, excessive dosage, inadequate monitoring, and ineffectual emergency care. Because of the relatively high incidence of life-threatening reactions and the complexity of the required emergency care, the routine use of pediatric sedation techniques that require large doses of narcotics cannot be advocated for use in the private office.

Relative potencies and durations of action with respect to respiratory depression of intravenous meperidine, fentanyl and alphaprodine in man.

Fentanyl, 0.7 and 1.4 microgram/kg, alphaprodine, 0.135 and 0.270 mg/kg meperidine, 0.564 and 1.127 mg/kg, and placebo were administered intravenously over 2.6 min by infusion to five healthy adult males. The crossover study was of incomplete Latin square design with at least 1 week between administrations of each study drug. The subjects breathed from a mixing chamber the gas composition of which was servo-controlled so as to produce CO2 ramps in the end-tidal gases. Each experiment was composed of: 1) control CO2 ramps, 2) a 25-min isocarbic run during which the drug was infused and 3) CO2 ramps at half-hour intervals for 3 hr postinfusion. The 20-liter intercept (the PETCO2 at which ventilation was 20 liters/min) was used as the measure of respiratory drive; the change in 20-liter intercept measured drug effect. The potency ratios at peak effect were: fentanyl/meperidine, 679; alphaprodine/meperidine, 3.68; fentanyl/alphaprodine, 179. With the area under the time-effect curves, the potency ratios of mean effect were: fentanyl/meperidine, 45c; alphaprodine/meperidine, 3.00; fentanyl/alphaprodine, 141. Thus, both fentanyl and alphaprodine are shorter-acting than meperidine, and fentanyl is shorter-acting than alphaprodine. The time-effect curves were fitted to linear and mono- and bi-exponential models. The time constants were compatible with the above relative durations of action.

[Synthesis and CNS-activity of spirocyclic pethidine and prodine analogs]. / Synthese und ZNS-Aktivität spirocyclischer Pethidin- und Prodin-Analoga.

The bromoacetals 5a and 5b react with n-butyllithium and the piperidone 7 to yield the hydroxyacetals 8b and 8c, respectively. Cyclization of 8b and 8c followed by acid hydrolysis affords the spirocyclic hemiacetals 10b and 10c which are oxidized by PCC to give the spirocyclic prodine analogues 4b and 4c. The corresponding spirocyclic pethidine derivative 2 is prepared by alkylation of the 2-benzopyran-3-one 16 with N-Lost (17). In the mouse writhing test the spiropethidine 2 is not analgesic active up to a dose of 20 mg/kg body weight (bw). In the spirocyclic prodine series the methylated lactone 4c is the most active analgesic with an ED50-value (ED50 = 9.2 mg/kg bw) in the range of the ED50-value of tramadol.