Structure determination of neoefrapeptins A to N: peptides with insecticidal activity produced by the fungus Geotrichum candidum.

The structures of neoefrapeptins A to N, peptides with insecticidal activity, were elucidated. They showed a close similarity to efrapeptin. However, all neoefrapeptins contained the very rare amino acid 1-amino-cyclopropane-carboxylic acid and some of them also contained (2S,3S)-3-methylproline. The neoefrapeptins are the first case, in which these amino acids are found as building blocks for linear peptides. They were identified by comparison of the silylated hydrolyzate to reference material by GC/MS (EI-mode). The sequence was elucidated using mass spectrometry (ESI+ mode). Full scan spectra showed two fragments in high yield, even under mild ionization conditions. MS/MS spectra of these two fragments yielded fragment rich spectra from which the sequence of the compounds was determined almost completely. The proteolytic cleavage with the proteinase papain yielded products that allowed to prove the rest of the sequence and the identity of the C-terminus to efrapeptin. The proteolytic cleavage products allowed furthermore to determine the position of the isobaric amino acids, pipecolic acid and 3-methylproline in neoefrapeptin F, as well as the location of R-isovaline and S-isovaline. Papain digestion was such established as a tool for structure elucidation of peptides rich in alpha,alpha-dialkylated amino acids. CD spectra suggested a 3(10) helical structure for neoefrapeptins A and F.

Chiral resolution of 1,3-dimethyl-4-phenylpiperidine derivatives using high-performance liquid chromatography with a chiral stationary phase.

A number of racemic 1,3-dimethyl-4-phenylpiperidines which serve as intermediates in the synthesis of opioid analgesics have been resolved on two commercially available high-performance liquid chromatography columns containing cellulose-based chiral stationary phases: Chiralcel OD and Chiralcel OJ. The resolution results were complementary between the two columns. Also, the polarity of substituents appears to play an important role on the ability of the Chiralcel OD column to resolve pairs of enantiomers.

[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.

Obstetrical medication and the newborn infant. II: The influence of meperidine (pethidine) on visual behaviour.

The visual fixation of two groups of healthy newborn infants was tested at a mean age of three days. Mothers of the infants in one group received a single dose of meperidine (pethidine) during labour and delivery; those in the second group received no medication. Unlike infants of mothers who received a single dose of alphaprodine hydrochloride in a previous study, there were no differences between the groups in the present study. Moreover, longer drug-to-delivery intervals did not appear to potentiate the effects of meperidine. A single dose of meperidine appears to have few effects on neonates' sensory functioning, which is contrary to other reports.

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.

GABAmimetics diminish antinociception of meperidine under conditions which enhance other opioid mu-agonists.

This study investigated the effects of pretreatment with muscimol (GABA-agonist) or diazepam (indirect GABAmimetic) on i.v. meperidine, fentanyl, alphaprodine and morphine, using rabbit tooth pulp and mouse hot plate assays. A previous study reported that the ED50 values for fentanyl in rabbits were significantly lowered by 0.25 mg/kg of muscimol (13.8 to 1.8 micrograms/kg) and by 1.5 mg/kg of diazepam (13.1 to 1.1 micrograms/kg). ED50 values for meperidine in rabbits in this study were increased by muscimol (1.2 to 3.2 mg/kg) and diazepam (1.5 to 3.1 mg/kg). ED50 values for fentanyl in mice were significantly lowered by 0.25 mg/kg of muscimol (23.0 to 8.9 micrograms/kg) and 1.0 mg/kg of diazepam (23.3 to 12.8 micrograms/kg). ED50 values for meperidine in mice were significantly increased by muscimol (2.1 to 5.0 mg/kg) and diazepam (2.0 to 4.8 mg/kg). ED50 values for alphaprodine and morphine were significantly lowered by muscimol and diazepam in mice. A higher dose of muscimol (1.0 mg/kg) had no effect on the ED50 values of meperidine in mice. The antinociception of a submaximal dose of meperidine in rabbits was significantly reduced by a 10 min pretreatment with i.v. diazepam (1.5 mg/kg) at 15, 20, 30 and 45 min after i.v. meperidine. The antinociception of a submaximal dose of fentanyl in rabbits was significantly increased by a 10 min pretreatment with i.v. diazepam (1.5 mg/kg) at 5, 10, 15 and 20 min after i.v. fentanyl. Pretreatment with 0.1 mg/kg of scopolamine enhanced the antinociceptive effect of a submaximal dose of fentanyl in both animal models. Diazepam reduced the antinociception produced by the combination scopolamine-fentanyl to that of fentanyl-vehicle control in both animal models. Pretreatment with 0.1 mg/kg of scopolamine did not change the magnitude of antinociception of a submaximal dose of meperidine in rabbits. Since meperidine possesses inherent anticholinergic activity, it is suggested that this anticholinergic activity may be involved in the reduction effects by muscimol and diazepam.

Obstetrical medication and the human newborn: the influence of alphaprodine hydrochloride on visual behaviour.

The visual habituation of two groups of newborn infants was tested at a mean age of 2.9 days with large achromatic squares of varying luminance. Mothers of the infants in one group received no medication during labour; mothers in the second group received a single dose of the synthetic narcotic alphaprodine hydrochloride. The two groups did not differ in the number of trials to reach the criterion, but newborns in the no-medication group fixated the stimuli for much longer periods than did infants in the alphaprodine group. First-fixation times of babies in the alphaprodine group were shorter when drug-to-delivery intervals were longer. These results, although tentative, imply that babies of medicated and unmedicated mothers differ in the manner in which they respond to visual stimuli.

The relationship between maternal labour analgesia and delay in the initiation of breastfeeding in healthy neonates in the early neonatal period.

An Infant Breastfeeding Assessment Tool was used to assess the breastfeeding behaviour of 38 healthy, full-term newborn babies of multiparous women from birth until effective feeding was established. After data collection was completed, the babies were divided into a non-medicated group (n = 18) and an alphaprodine group (n = 20) based upon the medication profile of the mother. Inter-group differences were analysed using ANOVA and Dunnett's t-test. The dependent variables were the hours from birth to establishing effective breastfeeding and IBFAT scores at 12, 24, 36 and 48 hours after birth. The findings suggest that even small doses of the narcotic analgesic alphaprodine, when administered 1 to 3 hours prior to delivery, can delay effective feeding by several hours and in some cases, days.

Conscious sedation for minor gynecologic surgery in the ambulatory patient. A pilot study.

A conscious sedation regimen consisting of alphaprodine, hydroxyzine, and methohexital together with intensive behavior modification was evaluated in an open pilot study for patients undergoing minor gynecologic surgery. This combination was found to result in hemodynamic stability, satisfactory patient compliance, and patient and surgeon acceptance. Patients were unable to recognize words taught to them just after drugs were administered.Electroencephalogram (EEG) changes seen in general anesthesia or deep sedation were not found in the EEG records of a subset of patients. These findings suggest that conscious sedation can provide adequate relief of pain and anxiety for minor gynecologic procedures when local anesthesia can achieve only partial pain relief.

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.

Effects of variable alphaprodine dose levels on arterial blood gases in rhesus monkeys.

The administration of alphaprodine submucosally in doses of 0.5, 1.0, and 1.5 mg/kg to ketaminized rhesus monkeys resulted in Po(2) levels significantly lower than those observed for controls (ketamine only) at the 10 min level. There was a significant increase in Po(2) levels between the 10 and 20 min intervals, thereafter, Po(2) levels returned toward normal and were not statistically different from baseline. Higher alphaprodine doses (1.0 and 1.5 mg/kg) resulted in a non-significant increase in Pco(2) values. Monitoring Po(2) levels during sedation seems preferable to monitoring Pco(2) in view of the findings of this study.

Respiratory arrest and prolonged respiratory depression after one low, subcutaneous dose of alphaprodine for obstetric analgesia. A case report.

Alphaprodine hydrochloride is an analgesic used commonly in the obstetric suite. A case of prolonged respiratory depression occurred after the administration of low-dose alphaprodine. Other cases of serious sequelae associated with the use of this drug have been reported on.