Structure-activity relationships (SAR) are studied in the series of 4,4-disubstituted piperidine morphinomimetics (42 compounds) by means of the Electronic-Topological Method (ETM). In the frameworks of this approach, its input data were taken as the results of conformational and quantum-mechanical calculations. These calculations had been carried out for all compounds from the series under study, taking into account their neutral and protonated by the nitrogen of piperidine cycle forms. The ETM application resulted in a set of pharmacophores and anti-pharmacophores, which formed a basis of a system used to predict analgesic activity. First of all, the system was tested on known analgesics. Testing has shown a good agreement with the experimental data. Then, the system was applied to a few compounds with similar structures but unknown activity. The results of the study could be used for computer screening and design of novel compounds with analgesics properties as new potential drugs.

Delirium is a common complication in hospitalized patients and is often associated with significant morbidity. It is important to recognize this syndrome early so that potential causes can be identified and properly managed. Although the etiology of delirium in critically or terminally ill patients is often multifactorial, opioid analgesics are often implicated as a potential underlying cause. Certain opioids, such as meperidine, have been identified as having a greater potential for causing delirium than others. There have been no published reports of anileridine-induced delirium and an illustrative case is presented.

This article describes our experience in the clinical use of nebulized opioids for the management of dyspnoea in patients with terminal cancer by reviewing three specific patient case studies in which this treatment was found to be both safe and effective in controlling breathlessness. The patients were treated with morphine, hydromorphone or anileridine in various doses according to their prior use of opioids. Additional formal studies are being initiated at this Centre.

The method for the analysis of anileridine, levorphanol, nalbuphine and ethamivan in urine by means of GC/NPD and GC/MSD is described. TFAA and MSTFA-MBTFA have been used in this procedure for TFA and TMS derivatization. The parent forms and the metabolites of the four drugs can be found by GC/NPD screening and GC/MSD confirmation. The method is reliable, fast and sensitive.

The analgesic effects of meperidine, anileridine, codeine and codeine + acetominophen on surgical and non-surgical pain in 101 patients were assessed using the McGill Pain Questionnaire. The quality of analgesia was determined by analyzing the changes in the pain descriptors chosen 1 hour after medication. Meperidine and anileridine differentially reduced pain qualities rated as "bright-phasic" by a student sample. Codeine and codeine + acetominophen produced similar patterns of analgesia that were homogeneous across "bright-phasic" and "dull-tonic" types of pain. The data suggest the possibility that opioids may differ in the quality of analgesia produced either as dose increases or different opioid receptor types are recruited.

Haemodynamic effects of equianalgesic doses of pethidine (1 mk kg -1) and anileridine (0.25 mg kg -1) were compared in patients with coronary artery disease, after induction of anaesthesia with flunitrazepam - N2O - pancuronium. Contrary to previous findings made in conscious patients, these analgesics produced a moderate circulatory depression. Heart rate, cardiac index and rate-pressure product were decreased by both drugs, and anileridine alone decreased mean arterial pressure. The only statistically significant differences in the haemodynamic changes between the two groups were those in pulmonary capillary wedge pressure and rate pressure product, which were slightly lower after anileridine than after pethidine.

Pigeons responded under a multiple fixed-ratio 30-response, fixed-interval 5-min schedule of food presentation. Daily administration of clorgyline (10 mg/kg, IM) tended to decrease rates of responding in both schedule components. Before daily clorgyline, tetrabenazine had no effect or decreased responding in the FI component at doses that markedly increased responding during chronic clorgyline. The clorgyline treatment resulted in a slight increase in sensitivity to the rate-decreasing effects of morphine, but no increased sensitivity to the rate-decreasing effects of meperidine, anileridine, alphaprodine, or fentanyl.

The haemodynamic effects of large bolus doses of metocurine 0.45 mg kg-1 and pancuronium 0.1 mg kg-1 were compared in patients with coronary artery disease anaesthetized with diazepam, anileridine and nitrous oxide. Hypotension occurred more frequently after metocurine and was a result of a decrease in systemic vascular resistance. After pancuronium there was no increase in arterial pressure or heart rate, but a small increase in cardiac index. The decrease in heart rate after metocurine was the principal cause of the statistically significant difference in cardiac index between the two groups. Contrary to previous findings, metocurine did not attenuate circulatory responses to tracheal intubation. During surgical stimulation, two of the 10 patients of the pancuronium group developed significant ST segment depression and three patients had a rate-pressure product greater than 12 000 mm Hg beat min-1. However, the difference in rate-pressure product between the groups was not statistically significant.

These studies were undertaken to determine the effects of morphine and other opiate and opioid agonists on body temperature in the mouse. Mice were lightly restrained, and rectal temperatures were monitored after injection of opiate analgesics at each of three ambient temperatures. The drugs tested were pure agonists representing eight different chemical classes. At 20 degrees C, morphine, hydromorphone, levorphanol, oxymorphone, methadone, etonitazene, fentanyl, etorphine and meperidine produced hyperthermia in low doses and hypothermia as the doses were raised. Codeine produced only hypothermia at 20 degrees C in the doses studied. At 25 degrees C, the hypothermic responses were greatly reduced in magnitude, and most drugs produced biphasic or only hyperthermic responses. At 30 degrees C, dose-related hyperthermia was the usual response with the exception of meperidine which produced only hypothermia, although a temperature increase was observed after anileridine, a closely related phenylpiperidine. There is good correlation between the relative potencies of the agonists with respect to their hypothermic effects in mice and their relative potencies as analgesics in mice. The temperature effects of morphine are complex but appear to be characteristic of opiate agonists as a class. The magnitude and the direction of the temperature responses to opiates are dose-dependent and profoundly influenced by the environmental temperature.

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.

The ability of pentobarbital, diazepam, and chlorpromazine to attenuate the rate-decreasing effects of a high dose (10 or 30 mg/kg) of meperidine was tested in pigeons responding under a multiple fixed-ratio, fixed-interval schedule of food presentation. Pentobarbital (10 mg/kg) attenuated the meperidine-induced rate decreases, whereas diazepam (0.3--3 mg/kg) or chlorpromazine (3--30 mg/kg) did not reliably attenuate the response rate decreases. The combination of 10 mg/kg of pentobarbital and meperidine resulted in a marked disruption of the pattern of responding in the fixed-interval component of the multiple schedule. Pentobarbital (1, 3, 10, and 17.5 mg/kg) was also tested in combination with rate-decreasing doses of normeperidine (17.5 mg/kg), anileridine (10 mg/kg), alphaprodine (10 mg/kg), and fentanyl (0.3 mg/kg). Pentobarbital reliably attenuated the rate-decreasing effects of normeperidine, anileridine, and alphaprodine, but not the rate decreases induced by fentanyl.

The separate and combined analgesic effects of 10 mg of oral amphetamine sulfate and 25 mg of oral anileridine dihydrochloride were studied in 24 healthy, adult, male volunteers. Tolerance of progressively increasing pain produced by the Submaximum Effort Tourniquet Technique was tested four times in each subject: after amphetamine, after anileridine, after the combination, and after a matching placebo. Treatments were administered double blind and in counterbalanced order. Elapsed time to report of slight, moderately distressing, very distressing, and unbearable pain was recorded on each trial. The four oral treatments differed significantly for very distressing and for unbearable pain. At each of the three upper pain levels, the mean tolerance times for anileridine and amphetamine were similar; each was longer than placebo but shorter than the combination; and the effect of the combination was approximately the sum of the effects of the two components.

The acute administration of levorphanol, morphine, anileridine, methadone, cyclazocine and pentazocine was found to increase brain levels of 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MOPEG-SO4) in rats. Drug-induced increases in brain levels of this norepinephrine metabolite were dose-dependent and peak drug effects generally occurred 1 hr after intraperitoneal injection. Six to 8 hr after opiate agonist or partial agonist administration, MOEG-SO4 levels returned to control values or below. The narcotic effect appeared to be stereospecific, since high doses of d-methadone and dextrorphan produced either no change or only minimal increases in brain MOPEG-SO4 levels when compared with saline-treated controls. The relative potency of the analgesics tested in producing increases in brain MOPEG-SO4 levels appeared to correlate reasonably well with the ability of these drugs to produce other characteristic pharmacological effects. The drug-induced increases in brain MOPEG-SO4 levels were antagonized by naloxone. The rate of disappearance of MOPEG-SO4 from the brains of animals treated with pargyline was not decreased by the opiate agonists or partial agonists tested indicating that these drugs did not inhibit the acid transport process. These results indicate that the production of an increase in brain norepinephrine turnover is a specific component of the pharmacological actions of narcotic analgesics.

The effects of anileridine, alphaprodine and fentanyl were studied on responding by pigeons under a multiple fixed-ratio, fixed-interval schedule of food presentation. Generally, all three drugs produced dose-related decreases in responding under both components of the multiple schedule, but rate increases were observed after low doses of anileridine and alphaprodine in some birds. Naloxone (1 mg/kg) antagonized the rate-increasing and rate-decreasing effects of doses of anileridine and alphaprodine of 10 mg/kg or less, whereas the effects of higher doses were not antagonized by naloxone. Likewise, chronic methadone or morphine (120 mg/kg/day p.o.) dosing produced only a slight cross-tolerance to the rate-decreasing effects of anileridine and alphaprodine. In contrast, naloxone (0.01, 0.1 and 1 mg/kg) and chronic methadone or morphine administration shifted the dose-effect curve for fentanyl to the right, indicating narcotic antagonism and methadone and morphine-induced cross-tolerance. These data indicate that the rate-decreasing effects of anileridine and alphaprodine are related only slightly to narcotic effects, whereas the rate-decreasing effects of fentanyl are primarily narcotic effects.

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.

A sensitive and specific radioimmunoassay for normeperidine has been developed that can detect as little as 100 pg of this metabolite. In competitive binding experiments with [125I]O-tyramyl-normeperidinic acid and an antiserum produced in rabbits immunized with a bovine serum albumin-normeperidinic acid conjugate, meperidine is only 0.01% as effective an inhibitor as normeperidine. Therefore, normeperidine can be determined in physiological fluids and in tissue extracts when relatively large amounts of meperidine or other N-phenylpiperidine esters are present. High pressure liquid chromatography can be used to confirm the results obtained by radioimmunoassay during the in vitro N-dealkylations of meperidine and anileridine to normeperidine. The normeperidine isolated by high pressure liquid chromatography accounts for all of the inhibitory reactivity determined in the enzymatic digests by the radioimmunoassay. Kinetic parameters (Km and Vmax) can be determined for the N-dealkylation of meperidine and anileridine. The formation of normeperidine with time can be followed in rabbits injected with meperidine or anileridine. Plasma levels may also be determined when meperidine is administered as an obsteric analgesic.

To test the hypothesis that the hyperpyrexia produced by meperidine and detromethorphan in rabbits pretreated with a monoamine oxidase inhibitor is related to inhibition of neuronal uptake of serotonin (5-hydroxytryptamine (5-HT)), fluoxetine (Lilly 110140) was studied. This potent and specific 5-HT neuronal uptake blocker was administered to phenelzine-pretreated rabbits and found to produce a lethal hyperpyrexia in doses equal to or greater than 2.5 mg/kg. The order of potency in blocking 5-[14C]HT uptake into synaptosomes prepared from rabbits was: fluoxetine greater than meperidine = dextromethorphan = levorphanol greater than anileridine greater than alphaprodine greater than morphine. Since fluoxetine, meperidine, and dextromethorphan produce hyperpyrexia in phenelzine-pretreated rabbits, whereas anileridine, alphaprodine, and morphine do not, there appears to be some correlation between the hyperpyrexic response and inhibition of 5-HT uptake. The exception is levorphanol, which is not hyperpyrexic despite being equipotent with meperidine and dextromethorphan in inhibiting 5-HT uptake. The ineffectiveness of levorphanol in producing hyperpyrexia may be due to its marked depressant properties, since the addition of another depressant drug (pentobarbital) antagonized the hyperpyrexic effect of meperidine.

The analgesic potency of anileridine compared with pethidine was found to be 4:1 by measuring the effect on withdrawal movements resulting from pinching of the skin or surgery during N2O + O2 anaesthesia. The potency ratio was examined postoperatively as well. Sixty patients who had undergone upper abdominal surgery with standard anaesthesia were studied in a double-blind, between-patient two dose comparison. Each patient and an observer graded the degree of pain relief. Here again, anileridine proved 4 times as potent as pethidine. With higher doses the response to anileridine was of shorter duration than was the response to pethidine. Respiratory depression was very similar after equianalgesic doses. Blood pressure and pulse rate remained stable. The total incidence of side effects was higher after pethidine.

Anileridine and pethidine have a spasmolytic action on animal intestine. Pethidine is known to have a spasmogenic effect at the choledocho-duodenal junction of man, but there is no study of the effect of anileridine on the biliary tract. In the present study the effects of anileridine and pethidine on the intracholedochal pressure during constant fluid perfusion in man were compared. The maximal elevation of the choledochal passage pressure was significantly greater after anileridine than after pethidine. However, the difference between anileridine and pethidine seemed to be less than that reported previously between morphine and pethidine. The effect of anileridine was of shorter duration than of pethidine. Anileridine and pethidine are not ideal analgesics when the normal activity of the biliary ductal system has to be maintained in pain or during cholangiography.

The circulatory effects of anileridine, a derivative of pethidine, have been little studied. Therefore we compared the haemodynamic effects of equianalgesic doses of pethidine (1 mg/kg i.v.) and anileridine (0.25 mg/kg) in matched patients requiring myocardial revascularization. Cardiac output was significantly increased 5 min after the administration of pethidine, mainly due to an increase in heart rate. A transient rise in the systolic pulmonary-arterial pressure was found after anileridine. No remarkable changes were found in systemic arterial pressures, central venous pressure, balloon-occluded pulmonary-arterial pressure, stoke volume, systemic or pulmonary vascular resistances and derived oxygen consumption. Further, 20 min after drug administration, there were no significant differences in any circulatory parameters between the two groups. One patient developed acute cardiac failure after anileridine, though as he had very severe coronary heart disease it remains an open question whether this was spontaneous or drug-induced. Since the rate-pressure product tended to increase after pethidine, this drug may not be considered an ideal analgesic for patients with ischaemic heart disease. Anileridine had less influence on this variable. Since the circulatory effects of pethidine seem to depend on the haemodynamic status of the patient, the haemodynamic properties of anileridine may also deserve further investigation.

Antibodies that bind an 125I-tyramyl derivative of N-succinylanileridine have been produced in animals immunized with N-succinylanileridine-hemocyanin conjugate. Several congeners and metabolites have been tested as competitors of this antigen-antibody reaction. The concentrations (in picomoles) required for 50% inhibition have been found to be: anileridine (0.2), meperidine (3.5), piminodine (3.8), diphenoxylate (20.5), normeperidine (20.0), meperidine acid (45,000) and anileridine acid (3,400). Although ester hydrolysis results in changes in inhibiting capacities on the order of 10(4), major structural changes in the substituent on the nitrogen of the piperidine ring are not readily recognized by the antibody. This radioimmunoassay can be used to study a variety of N-substituted phenylpiperidine carboxylic acid esters by relating the results to the standard curve obtained for the drug under investigation. For all practical purposes, alphaprodine, morphine and methadone do not interfere with the assay.

Anileridine and pethidine were established by gas and thin layer chromatography and mass spectroscopy. In the mass spectrum the main peak of anileridine is found at m/e 246 and that of pethidine at m/e 71. The determination was made by gas chromatography from the blood, urine, liver, muscle and stomach contents.

The analgesic potency of anileridine and pethidine was compared in 28 patients by measuring their effect on withdrawal movements caused by pinching of the skin or by surgery during N2O + O2 anaesthesia. It appeared that anileridine is 3.5 to 4 times as potent as pethidine on a weight basis. In equianalgesic doses the incidence of side effects was equal after both drugs.

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.