Search

A series of benzyl esters of meperidine and normeperidine were synthesized and evaluated for binding affinity at serotonin, dopamine and norepinephrine transporters. The 4-methoxybenzyl ester 8b and 4-nitrobenzyl ester 8c in the meperidine series and 4-methoxybenzyl ester 14a in the normeperidine series exhibited low nanomolar binding affinities at the SERT (K(i) values <2nM) and high SERT selectivity (DAT/SERT >1500 and NET/SERT >1500)., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Topical analgesics have many potential advantages over systemic administration. Prior work has shown potent analgesic activity of a number of topical opioids in the radiant heat tail-flick assay. The current study confirms the analgesic activity of morphine and extends it to two other mu opioids, methadone and meperidine. Combinations of topical morphine and lidocaine are synergistic. Similarly, the combination of methadone and lidocaine is synergistic. While there appeared to be some potentiation with the combination of meperidine and lidocaine, it did not achieve significance. Systemically, prior studies have shown that co-administration of morphine and methadone was synergistic. The combination of morphine and methadone was also synergistic when given topically. In contrast, the combination of morphine and meperidine was not synergistic systemically and it was not synergistic topically. Thus, the pharmacology of topical opioids mimics that seen with systemic administration. Their activity in the topical model supports their potential utility while the local limitation of their actions offers the possibility of a reduced side-effect profile., ((c) 2010 Elsevier B.V. All rights reserved.)

alpha(2)-adrenoceptor agonists like clonidine or dexmedetomidine increase the sedative and analgesic actions of opioids. Furthermore opioids like meperidine show potent anti-shivering effects like alpha(2)-adrenoceptor agonists. The underlying molecular mechanisms of these effects are still poorly defined. The authors therefore studied the ability of four different opioids (meperidine, remifentanil, sufentanil and tramadol) to interact with different alpha(2)-adrenoceptor subtypes in mice lacking individual alpha(2A)-, alpha(2B)- or alpha(2C)-adrenoceptors (alpha(2)-adrenoceptor knock out (alpha(2)-AR KO) mice)). The interaction of opioids with alpha(2)-adrenoceptors was investigated by quantitative receptor autoradiography in brain slices of alpha(2A)-, alpha(2B)- or alpha(2C)-adrenoceptor deficient mice. Displacement of the radiolabelled alpha(2)-adrenoceptor agonist [(125)I]-paraiodoclonidine ([(125)I]-PIC) from alpha(2)-adrenoceptors in different brain regions by increasing opioid concentrations was measured, and binding affinity of the analysed opioids to alpha(2)-adrenoceptor subtypes in different brain regions was quantified. Meperidine, remifentanil and tramadol but not sufentanil provoked dose dependent displacement of specifically bound [(125)I]-PIC from all alpha(2)-adrenoceptor subtypes in cortex, cerebellum, medulla oblongata, thalamus, hippocampus and pons. Required concentrations of meperidine and remifentanil for [(125)I]-PIC displacement from alpha(2B)- and alpha(2C)-adrenoceptors were lower than from alpha(2A)-adrenoceptors, indicating higher binding affinity for alpha(2B)- and alpha(2C)-adrenoceptors. In contrast, [(125)I]-PIC displacement by tramadol indicated higher binding affinity to alpha(2A)-adrenoceptors than to alpha(2B)- and alpha(2C)-adrenoceptors. Our results indicate that meperidine, remifentanil and tramadol interact with alpha(2)-adrenoceptors in mouse brain showing different affinity for alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptors. In contrast, the micro-agonist sufentanil did not show any alpha(2)-adrenoceptor interaction. These effects may have an impact on the pharmacologic actions of these opioids.

The structure-activity relationships of 3',4'-dichloro-meperidine were investigated at dopamine (DAT) and serotonin transporters (SERT). Large ester substituents and lipophilic groups at the 4-position favored molecular recognition at the SERT. The benzyl ester of 3',4'-dichloro-meperidine exhibited high potency and high selectivity for the SERT (DAT/SERT=760). Chemical modification of the ester group and N-substitution generally led to compounds with decreased DAT affinity. Only small esters and alkyl groups were tolerated at the 4-position of the meperidine ring system by the DAT. Overall, the meperidine analogues were generally more selective for the SERT than for the DAT.

The efflux transporter P-glycoprotein (P-gp) is an important component of the blood-brain barrier (BBB) that limits accumulation of many compounds in brain. Some opioids have been shown to interact with P-gp in vitro and in vivo. Genetic or chemical disruption of P-gp has been shown to enhance the antinociceptive and/or toxic effects of some opioids, although the extent of this phenomenon has yet to be understood. The purpose of this study was to assess quantitatively the influence of mdr1a P-gp on initial brain uptake of chemically diverse opioids in mice. The brain uptake of opioids selective for the mu (fentanyl, loperamide, meperidine, methadone, and morphine), delta (deltorphin II, DPDPE, naltrindole, SNC 121) and kappa (bremazocine and U-69593) receptor subtypes was determined in P-gp-competent (wild-type) and P-gp-deficient [mdr1a(-/-)] mice with an in situ brain perfusion model. BBB permeability of the opioids varied by several orders of magnitude in both mouse strains. The difference in brain uptake between P-gp-competent and P-gp-deficient mice ranged from no detectable effect (meperidine) to >/=8-fold increase in uptake (DPDPE, loperamide, and SNC 121). In addition, loperamide efflux at the BBB was inhibited by quinidine. These results demonstrate that P-gp modulation of opioid brain uptake varies substantially within this class of compounds, regardless of receptor subtype. P-gp-mediated efflux of opioids at the BBB may influence the onset, magnitude, and duration of analgesic response. The variable influence of P-gp on opioid brain distribution may be an important issue in the context of pharmacologic pain control and drug interactions.

Much evidence points to the involvement of N-methyl-D-aspartate (NMDA) receptors in the development and maintainance of neuropathic pain. In neuropathic pain, there is generally involved a presumed opioid-insensitive component, which apparently can be blocked by NMDA receptor antagonists. However, in order to obtain complete analgesia, a combination of an NMDA receptor antagonist and an opioid receptor agonist is needed. Recent in vitro data have demonstrated that methadone, ketobemidone, and dextropropoxyphene, in addition to being opioid receptor agonists, also are weak noncompetitive NMDA receptor antagonists. Clinical anecdotes suggest that the NMDA receptor antagonism of these opioids may play a significant role in the pharmacological action of these compounds; however, no clinical studies have been conducted to support this issue. In the present commentary, we discuss evidence for the NMDA receptor antagonism of these compounds and its relevance for clinical pain treatment; an overview of structure-activity relationships for the relevant opioids as noncompetitive NMDA receptor antagonists also is given. It is concluded that although the finding that some opioids are weak noncompetitive NMDA receptor antagonists in vitro has created much attention among clinicians, no clinical studies have been conducted to evaluate the applicability of these compounds in the treatment of neuropathic pain conditions.

Meperidine has atypical opioid receptor agonist effects and shares some structural features with the phenyltropane (WIN) analogs of cocaine. In combination with 0.1 mg/kg naltrexone, meperidine produced cocaine-like discriminative stimulus effects in monkeys, whereas morphine was inactive. Both cocaine and meperidine inhibited [3H]dopamine uptake in chopped rat caudate putamen with comparable potencies; meperidine differed from cocaine in that its effects could be characterized as having predominantly a single high-affinity component. Morphine was not active in inhibiting [3H]dopamine uptake, indicating that the effect of meperidine was not via a classic mu-opioid receptor agonist action. Further, meperidine but not morphine displaced [3H]WIN 35,428 (2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane) binding. These data suggest that the actions of meperidine that are atypical of opioids are due to activity at the dopamine transporter. In addition, meperidine appears to interact predominantly with the high-affinity component of the dopamine transporter, and this high-affinity component may be the site of importance for the production of cocaine's behavioral effects.

Interaction of neuroleptic drugs with the opiate receptors was investigated by inhibition of the stereospecific binding of 3H-naloxone. Benperidol and pimozide, with IC50's of 0.3-0.5 muM, were more potent than the classical opiates meperidine and propoxyphene. A systematic structure-activity relationship was evident with the basic opiate structure of a benzene and a piperidine ring preserved in active compounds. No correlation between neuroleptic activity and binding to the opiate receptor was demonstrated.

Either pethidine HCl (50 mg/kg s.c.) or methadone HCl (8 mg/kg s.c.) produced a prominent decrease in locomotor activity of rats. Pretreatment of rats with p-chlorophenylalanine (p-CPA, 320 mg/kg i.p.) 48 h before the narcotic injection significantly antagonized the activity-decreasing effects of narcotics. When rats pretreated with p-CPA were given 5-hydroxytryptophan (75 mg/kg s.c.) 30 min before narcotic administration, the activity-decreasing response to narcotics was restored. Thus, a decrease in locomotor activity induced in rats by either pethidine or methadone is probably mediated by serotonergic mechanisms.

The effects of denervation or pretreatment with reserpine or 6-hydroxydopamine on the contractile responses of the cod spleen have been studied. The contraction produced by tyramine is abolished by pretreatment with reserpine or 6-hydroxydopamine and by denervation. The response to tyramine is restored in reserpine-treated strips after exposure to noradrenaline, but this is not the denervated or 6-hydroxydopamine-treated strips. The response to noradrenaline is potentiated by 6-hydroxydopamine treatment or denervation, while neither acute (2 days) nor chronic (8 days) reserpine treatment have any detectable effect. The effects of 6-hydroxydopamine and denervation are probably due to specific supersensitivity caused by the loss of the presynaptic uptake mechanisms on destruction of the nerve terminals, but contribution by a non-specific postsynaptic supersensitivity is not completely excluded. The effect of acetylcholine is also significantly potentiated by pretreatment with 6-hydroxydopamine or denervation, but not by reserpine, while the dose-response curve for carbachol is not affected by the specific cholinesterase inhibitor BW 284 C51, denervation or 6-hydroxydopamine. The degree of potentiation of the acetylcholine curve caused by both denervation and 6-hydroxydopamine treatment is very similar to that produced by BW 284 C51. It is concluded therefore, that the cholinesterase is associated with nerve fibres which are destroyed by denervation and 6-hydroxydopamine. Although the cod spleen receives both cholinergic and adrenergic sympathetic innervation all responses to nerve stimulation of the perfused spleen are abolished after 6-hydroxydopamine treatment. The possibility is suggested that the sympathetic fibres to the cod spleen represent a primitive type of neuron, with both catecholamines and acetylcholine present within the same terminals.

The purpose of the present study was to compare several central nervous system (CNS) depressant drugs in their ability to attenuate the suppressant effects of normeperidine on the responding of pigeons under a multiple fixed-ratio, fixed-interval schedule of grain presentation. The effects of pentobarbital (3 and 10 mg/kg i.m.), diazepam (1-10 mg/kg p.o.), clonazepam (0.03-3 mg/kg p.o.), aminooxyacetic acid (1-10 mg/kg i.m.), baclofen (5 and 10 mg/kg i.m.) and ethanol (0.5-2 g/kg p.o.) were determined alone and in the presence of 17.5 mg/kg (p.o.) of normeperidine, a dose which almost completely eliminates responding. Pentobarbital, diazepam and clonazepam attenuated the normeperidine-induced suppression of behavior, whereas aminooxyacetic acid, baclofen and ethanol failed to attenuate the effects of normeperidine. The results indicate that in the pigeon the non-opioid effects of normeperidine and related analogs are related to proconvulsive actions.

The effect of opiate analgesics (omnopon, pethidine, pentazocine) on the urethral mucosal sensitivity threshold in 37 patients, and of the potent opiate/opioid antagonist naloxone on 10 volunteers is described. Omnopon and pentazocine caused a significant decrease in sensitivity (p less than 0.02) and naloxone caused a significant increase in sensitivity (p less than 0.02). The results confirm a role for the endogenous opioids in modulating urethral sensitivity, and the implications of this are discussed.

The involvement of brain 5-hydroxytryptamine (5-HT), noradrenaline and dopamine in the antinociceptive activities of pethidine and morphine has been compared in the mouse. Differences have been shown in the activities of pethidine and morphine in mice treated with either 5-hydroxytryptophan or reserpine. No differences between the activities of pethidine and morphine were demonstrated in mice treated with either alpha-methyl-p-tyrosine, L-dopa or p-chlorophenylalanine. In reserpinised mice, pethidine's antinociceptive activity was either potentiated, unaffected or antagonised, dependent upon the reserpine dose schedule. Pethidine was shown to be able to raise brain 5-HT concentrations in reserpinised mice. This effect was also dependent upon the reserpine dose schedule used. Morphine, which was antagonised by all reserpine dose schedules, did not raise noradrenaline or dopamine in control or reserpinised mice. Although the reserpine schedule, which potentiated pethidine's antinociceptive activity, was the same as that in which pethidine had the most marked effects upon 5-HT, no definite connections between the two observations could be made. Naloxone abolished the antinociceptive activity of pethidine in reserpinised mice, but not the rise in 5-HT.

For 6 large series of compounds derived from the piperidine moieties of spiperone, pimozide, haloperidol, pethidine, fentanyl and 4-methocarboxy-fentanyl, IC50 values were determined in the opiate and neuroleptic binding assay using [3H]-fentanyl and [3H]-haloperidol as ligands, respectively. The specificity and difference between both receptors were demonstrated on the basis of several criteria (1) the sterospecificity of the binding (2) the significant correlation between the in vitro activity of the drugs and their pharmacological potency in vivo, not withstanding some discrepancies which are probably of pharmacokinetic and/or metabolic origin (3) the ability to discriminate between morphinomimetic and neuroleptic drugs by the differential affinity for their specific receptro (4) the structure--activity relationships derived from the in vitro data indicating that the structural requirements for high affinity binding in vitro parallel those for high in vivo potency (5) a demonstration, on the basis of physicochemical principles, of the difference in binding mechanism between morphinomimetics and neuroleptics to their respective receptor.

The effect of morphine, methadone and pethidine injected into the cerebral ventricle of the unanesthetized cat upon emesis produced by nicotine induced similarly was investigated. Morphine and morphine-like drugs depress or abolish the emetic effect of nicotine. The inhibitory effect of morphine, methadone and pethidine is observed after a transient emetic action of these drugs. The emetic and anti-emetic action of morphine, methadone and pethidine can perhaps be ascribed to an agonist/antagonist activity. Further, the possible site of inhibitory action of morphine and morphine-like drugs on the emesis produced by nicotine may be the area postrema of fourth ventricle.

In pigeons trained to discriminate between morphine (10 mg/kg) and saline, both morphine and ethylketazocine produced dose-related morphine-appropriate responding. The maximum effect produced by meperidine, however, was only 60% of that produced by morphine or ethylketazocine. Naltrexone (0.1-1.0 mg/kg) produced dose-related shifts to the right in the dose-response curves for the discriminative stimulus and rate-decreasing effects of morphine and ethylketazocine without affecting the response produced by meperidine. Thus, in contrast to the effects observed in other species, morphine and ethylketazocine produce similar discriminative effects in the pigeon. In addition, the morphine-like discriminative effects and the rate-decreasing effects of meperidine in the pigeon are not mediated by the naltrexone-sensitive mechanisms which mediate these effects of morphine or ethylketazocine.

Several drugs that are utilized primarily for their effects on the central nervous system also affect lower urinary tract function. Most of these effects are produced by the action of these drugs on adrenergic and cholinergic receptors or by direct action of lower urinary tract musculature. Central nervous system stimulants and depressants which are known to affect the storage or evacuation role of the lower urinary tract are discussed.