Sufentanil, a very potent and extremely safe intravenous morphine-like compound in mice, rats and dogs.

Sufentanil (R 30 730), N-[4-methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide, is a chemically novel, highly potent and extremely safe intravenous morphine-like agent in laboratory animals. In mice R 30 730 i.v. is 2304 times more potent than morphine (hot plate ED50's: 0.0028 and 6.45 mg/kg, respectively). The i.v. safety margin of R 30 730 in mice is 1 : 6 679 (LD50 = 18.7 mg/kg). Under the same experimental conditions the safety margin of pethidine is 1 : 7.97, of morphine 1 : 34.9 and of fentanyl 1 : 454. In rats R 30 730 i.v. is 4521 times more potent than morphine (tail withdrawal test ED50's: 0.00071 and 3.21 mg/kg, respectively). The i.v. safety margin of R 30 730 in rats is 1 : 25 211 (LD50 : 17.9 mg/kg). Under the latter experimental conditions the safety margin of pethidine is 1 : 4.80, of morphine 1 : 69.5 and of fentanyl 1 : 277. In dogs R 30 730 i.v. is 2429 times more potent than morphine (apomorphine antagonism test ED50's: 0.00028 and 0.68 mg/kg, respectively). The i.v. safety margin in dogs is approximately 1 : 50 000, the LD50 being +/- 14.0 mg/kg. All morphine-like effects of R 30 730 are immediately antagonized by nalorphine. These pharmacological findings are relevant in connection to the increasing interest for use of morphinomimetics in anesthesia.     

Synthetic analgesics: N-(1-[2-arylethyl]-4-substituted 4-piperidinyl) N-arylalkanamides.

The synthesis of several 4-arylamino-4-piperdinecarboxylic acids is reported. These acids were starting materials for the preparation of alpha-amino esthers, ethers and ketones. Different synthetic approaches are described. Suitable substitution on both nitrogen atoms afforded extremely potent analgesics. Thus, methyl 4-[N-(1-oxopropyl)-N-phenylamino]-1-(2-phenylethyl)-4-piperidinecarboxylate (22),N-(4-(methoxymethyl)-2-[2-(2-thienyl)ethyl]-4-piperidinyl)-N-phenylpropranamide (67) and N-[4-acetyl-1-(2-phenylethyl)-4-piperidinyl]-N-phenylpropanamide (82) were found to be respectively 7682, 3987 and 4921 times as potent as morfine. Both cis- and trans-3-methyl homologs of 22 have been prepared. As expected, analgesic activity resides mainly in the cis-isomer.     

强效镇痛剂研究——Ⅱ.3-甲基芬太尼类衍生物的合成及镇痛活性

本文报道了N-[1-(β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺(7209)和N-[1-(β-羟基-β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺(7302)等一系列3-甲基芬太尼类衍生物的合成及镇痛活性。绝大部分该类衍生物均具有典型的吗啡样镇痛活性,是一类结构较简单、易于合成、镇痛作用极强的麻醉镇痛剂。化合物7302的ED₅₀为0.0022mg/kg(ip,小鼠,热板法),比芬太尼强28倍,竟达吗啡的6318倍,为我们至今合成该类衍生物中作用最强者。     

4-甲氧羰基-4-N-丙酰苯胺基哌啶1位衍生物的合成及其镇痛作用

本文报道了一系列N-[-1(2-苯乙基-4-甲氧羰基-4-哌啶基]-N-丙酰苯胺(4-甲氧羰基芬太尼)哌啶环1位取代衍生物的合成及其镇痛活性;讨论了结构与镇痛活性之间的关系。药理试验结果表明,大部分化合物具有典型的吗啡样镇痛活性,是一类作用极强的麻醉性镇痛剂。特别是哌啶环1位β-苯环被取代乙烯基替代的化合物具有相当或接近子母体化合物的镇痛活性。其代表物1321的镇痛活性(ED_(50)=0.005mg/kg ip,小鼠,热板法)略强于4-甲氧羰基芬太尼(ED_(50)=0.0063 mg/kg)。     

4-取代芬太尼类化合物的晶体结构和构效关系

以芬太尼为典型代表物的4-苯胺哌啶类化合物是一类具有独特结构类型、强度高、作用迅速的高效麻醉镇痛剂。该类化合物哌啶环的3位或4位引入适当取代基团能提高镇痛活性,其活性强度已达微克水平。芬太尼类化合物的构效关系研究表明:分子构象与生物活性之间关系密切。虽Peeters和Koch等人分别对芬太尼(R 4263)和4-甲氧甲基芬太尼类代表物(R 30490,R 30730)     

Alfentanil (R 39 209) — a particularly short-acting intravenous narcotic analgesic in rats

Alfentanil, N-{1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-l-yl)ethyl]-4-(methoxymethyl)-4-piperidinyl}-N-phenyl propanamide monohydrochloride monohydrate, is a chemically novel, potent, extremely short-acting and safe intravenous morphine-like agent in laboratory animals. As an analgesic in rats, alfentanil is 137 times as potent as pethidine (tail withdrawal reaction test: i.v. ED50 is 6.04 mg/kg for pethidine and 0.044 mg/kg for alfentanil). The safety margin in rats is 1,080 (LD50: 47.5 mg/kg i.v.). Alfentanil reaches its peak effect within 2 min after injection, and its duration of action is very short: at two times its lowest ED50 the drug has a duration of action of 10 min. This duration is 30–35 min for pethidine and fentanyl, and 120 min for morphine. The narcotic antagonist naloxone produces an immediate and complete reversal of all morphine-like effects of alfentanil. In dogs, alfentanil is a potent antiemetic (ED50: 0.032 mg/kg i.v.) with a safety margin of over 850 (LD50: > 20 mg/kg i.v.).     

Metabolism of alfentanil by isolated hepatocytes of rat and dog

1. The biotransformation of ³H-alfentanil was studied using suspension cultures of isolated hepatocytes of male and female rats and of dogs.

2. In hepatocytes of the male rat, alfentanil was readily metabolized, following linear Michaelis-Menten kinetics over the concentration range 5—400μM. The metabolism was strongly inhibited by the cytochrome P-450 inhibitors metyrapone, α-naphthoflavone and piperonyl butoxide.

3. The major metabolites of alfentanil, which were formed in suspension cultures of male rat hepatocytes, were identified by h.p.l.c. co-chromatography and by mass spec-trometry and included N-[4-(hydroxymethyl)-4-piperidinyl]-N-phenylpropanamide. N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide or noralfentanil and N-[1-[2-(4-ethyl-4,5-dihydro-5-oxo-1-H-tetrazol-1-yl)ethyl]-4-(hydroxymethyl)-4-piperidinyl]-N-phenylpropanamide or desmethylalfentanil.

4. The major in-vitro metabolic pathways of alfentanil in hepatocytes of the three sources were oxidative N-dealkylation at the piperidine nitrogen and oxidative O-demethylation at the methoxymethyl moiety.     

New 1-(heterocyclylalkyl)-4-(propionanilido)-4-piperidinyl methyl ester and methylene methyl ether analgesics.

A series of new 1-(heterocyclyalkyl)-4-(propionanilido)-4-piperidinyl methyl esters and methylene methyl ethers have been synthesized and pharmacologically evaluated. In the mouse hot-plate test, the majority of compounds exhibited an analgesia (ED50 less than 1 mg/kg) superior to that of morphine. These studies revealed a pharmacological accommodation for many more structurally diverse and far bulkier aromatic ring systems than the corresponding components of the arylethyl groups of the prototypic methyl ester (carfentanil, 2) and methylene methyl ether (sufentanil, 3 and alfentanil, 4) 4-propionanilido analgesics. Compound 9A (methyl 1-[2-(1H-pyrazol-1-yl)-ethyl]-4-[(1-oxopropyl)phenylamino]-4- piperidinecarboxylate), which exhibited appreciable mu-opioid receptor affinity, was a more potent and short-acting analgesic, than alfentanil with less respiratory depression in the rat. On the other hand, the phthalimides 57A and 57B, which exhibited negligible affinity for opioid receptors associated with the mediation of nociceptive transmission (i.e., mu-, kappa-, and delta-subtypes), displayed analgesic efficacy in all antinociception tests. In addition, while 57B, compared to clinical opioids, showed a superior recovery of motor coordination after regaining of righting reflex from full anesthetic doses in the rat rotorod test, 57A showed significantly less depression of cardiovascular function at supraanalgesic doses in the isoflurane-anesthetized rat.     

Analgesic activity and pharmacological characterization of N-[1-phenylpyrazol-3-yl]-N-[1-(2-phenethyl)-4-piperidyl] propenamide, a new opioid agonist acting peripherally

We previously reported the synthesis of three new opioid agonists as well as their in vitro and in vivo activity [Girón, R., Abalo, R., Goicoechea, C., Martín, M.I., Callado, L.F., Cano, C., Goya, P., Jagerovic, N. 2002. Synthesis and opioid activity of new fentanyl analogs. Life Sci. 71, 1023-1034]. One of them, N-[1-phenylpyrazol-3-yl]-N-[1-(2-phenethyl)-4-piperidyl)] propenamide (IQMF-4), showed an interesting antinociceptive activity. Intraperitoneally (i.p.) administered, it was as effective as fentanyl or morphine, being less potent than fentanyl but more so than morphine. The aim of the present work was to evaluate its antinociceptive effect by different routes of administration, using the hot plate test, and to investigate possible side effects, such as tolerance and withdrawal, in vitro, using the myenteric plexus-longitudinal muscle strip preparation from guinea pig ileum, and in vivo, using the hot plate test. IQMF-4 was more potent than morphine when administered per os (p.o.), but less potent when administered intracerebroventricularly (i.c.v.). By both routes, fentanyl is more potent that IQMF-4. When IQMF-4 was administered i.p., naloxone methiodide, a peripherally acting antagonist, was able to completely block its antinociceptive effect, whereas, after i.c.v. administration, the blockade was only partial. An interesting feature of the new compound is that it induces tolerance in vitro but not in vivo. Moreover, though in vitro withdrawal was not different from fentanyl or morphine, in vivo withdrawal symptoms were significantly less frequent in mice treated with IQMF-4 than in those treated with morphine or fentanyl. Although more assays are required, these results show that IQMF-4 appears to be a potent analgesic compound with an interesting peripheral component, and reduced ability to induce dependence.     

Synthesis and structure-activity relationships of 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives having narcotic agonist and antagonist activity

Racemates and enantiomers of 1-substituted 4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine derivatives (3-18) were synthesized, and their analgesic and other pharmacological activities and structure-activity relationships were investigated. The S-(+) enantiomers of 2a, 5, 7, 9, 10, and 15-18 had a stronger analgesic activity than their R-(-) enantiomers; analgesic activity of the strongest one [(S)-(+)-10] was 105 times as potent as that of morphine. The S-(+) enantiomers of these compounds had the opposite configuration to that of morphine with respect to its (C-9) asymmetric center but the same configuration to that of the tyrosine residue of Met5-enkephalin. The R-(-) enantiomers of 16 and 18 showed narcotic antagonist activity, but the S-(+) enantiomers did not. (R)-(-)-18 had analgesic and narcotic antagonist activities comparable to pentazocine but showed no significant physical dependence liability. From these results, it is suggested that these compounds show an uncommon enantioselectivity in comparison with morphine and its surrogates, and belong to a new series of compounds having a potent analgesic activity.     

Biotransformation of sufentanil in liver microsomes of rats, dogs, and humans

The biotransformation of sufentanil (SUF), an analog of the synthetic opioids fentanyl and alfentanil, was investigated in liver microsomes of rats, dogs, and humans. The drug was extensively metabolized and the metabolism was found to be very similar, both kinetically and metabolically, in the three species. The initial metabolism of SUF occurred monophasically in man and dog and biphasically in the rat over a concentration range of 0.13-20.1 microM. The apparent Vm values were 7.30 and 6.15 nmol metabolized.min-1.mg protein-1, and the apparent Km values were 4.98 microM and 15.2 microM for dog and human microsomes, respectively. In rat microsomes, apparent Km values were 0.10 and 20.8 microM, and the apparent Vm values were 0.10 and 7.32 nmol metabolized.min-1.mg protein-1 for the high and low affinity site, respectively. The major metabolic pathways were similar in the three species and included oxidative N-dealkylation at the piperidine nitrogen, oxidative N-dealkylation of the piperidine ring from the phenylpropanamide nitrogen, oxidative O-demethylation, and aromatic hydroxylation. Desmethyl-SUF was formed at the shorter incubation times but quickly metabolized into secondary metabolites. The major metabolites which could be detected at the end of the incubation were N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide, N-[4-(hydroxymethyl)-4-piperidinyl]-N-phenylpropanamide, and N-phenylpropanamide. The relevance of the in vitro results is discussed in relation to previous in vivo studies of the metabolism of SUF in rats, dogs, and humans.     

New 4-(heteroanilido)piperidines, structurally related to the pure opioid agonist fentanyl, with agonist and/or antagonist properties

A research program based on certain heterocyclic modifications (12-50) of the fentanyl (1) molecule has generated a novel class of opioids. In the mouse hot-plate test, these compounds were weaker analgesics than 1. Two types of antagonists were observed in morphine-treated rabbits: those (e.g., 28) that reversed both respiratory depression and analgesia and those (e.g. 32) that selectively reversed respiratory depression. Evaluation of in vitro binding affinities to rat brain opioid receptors was inconclusive for a common locus of action for the agonist as well as the antagonist component. Further pharmacological evaluation of 32, N-(2-pyrazinyl)-N-(1-phenethyl-4-piperidinyl)-2-furamide, in the rat showed it to be a potent analgesic (ED50 = 0.07 mg/kg, tail-flick test) with little cardiovascular and respiratory depression when compared to fentanyl.     

Synthesis and in vitro opioid receptor functional antagonism of analogues of the selective kappa opioid receptor antagonist (3R)-7-hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic)

In previous structure-activity relationship (SAR) studies, we identified (3 R)-7-hydroxy- N-((1 S)-1-{[(3 R,4 R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic, 1) as the first potent and selective kappa opioid receptor antagonist from the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonist. In the present study, we report the synthesis and in vitro opioid receptor functional antagonism of a number of analogues of 1 using a [ (35) S]GTPgammaS binding assay. The results from the studies better define the pharmacophore for this class of kappa opioid receptor antagonist and has identified new potent and selective kappa antagonist. (3 R)-7-Hydroxy- N-[(1 S,2 S)-1-{[(3 R,4 R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylbutyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide ( 3) with a K e value of 0.03 nM at the kappa receptor and 100- and 793-fold selectivity relative to the mu and delta receptors was the most potent and selective kappa opioid receptor antagonist identified.     

Synthesis and antinociceptive activity of some novel nonpeptide derivatives of interleukin-1 beta (193-195) sequence

The synthesis of a new series of nonpeptide derivatives of interleukin-1 beta sequence is described. Compounds have been investigated for their relative activity regarding antinociception and suppression of inflammation. Several compounds with R1(R)Lys [CH2N]-Pro structure showed better efficacy in the inflamed paw pressure test than indometacin and morphine. In terms of the relative potencies the above mentioned products (i.e. compounds 2, 4, 5, 6; ED50 values of 0.002, 0.0035, 0.0032, 0.0074 mg/kg i.p. respectively) were 10-100 times more potent than indometacin and morphine (ED50 values of 0.22 and 0.75 mg/kg). Compounds 1-14 were not able to inhibit binding of labeled interleukin-1 beta to EL 4-6.1 murine cells, since they had no affinity for interleukin-1 beta receptors. The antinociceptive activity elicited by compound 4 in the rat inflamed paw pressure test was inhibited by naloxone, but the compound was inactive in the mouse hot plate and rat paw pressure tests. These results suggest that compound 4 exerts its antinociceptive activity through a mechanism which is based on the local release of endogenous opioids in injured tissue.     

The major metabolite of fentanyl in the horse

Fentanyl, a potent, synthetic narcotic analgesic, has reportedly been used to "dope" racehorses. Urine was collected from a horse dosed with 70 mg of [3H]fentanyl, and the primary metabolite, a water-soluble, amphoteric compound, was isolated by high-pressure liquid chromatography and identified by spectroscopic analysis. This metabolite was found to be N-[1-(2-phenethyl-4-piperidinyl)] malonanilinic acid.     

Antisecretory and antiulcer activities of a potent new histamine H2-receptor antagonist with an intermediate duration of action

The antisecretory activities of 4-(dimethylamino)- N-[2-[3-[3-(1-piperidinyl)methyl]phenoxy]propyl]amino]- 1,2,5-thiadiazol-4-yl]amino]ethyl]-butanamide, S-oxide (AY-29,315) and ranitidine were determined in the rat, dog and monkey. In conscious, chronically cannulated rats, AY-29,315 was 10 and 208 times more potent than ranitidine as an inhibitor of spontaneous gastric acid secretion by the p.o. and i.v. routes, respectively. Tolerance did not develop in the conscious rat with either compound when administered for 8 consecutive days at doses equivalent to 4 times their antisecretory ED50. In lumen-perfused, anesthetized rats, AY-29,315 i.v. was 44 times more potent than ranitidine as an inhibitor of dimaprit-induced acid secretion. In the gastric fistula dog, AY-29,315 was 7.5 times more potent than ranitidine as an inhibitor of dimaprit-induced secretion by the i.v. route but 3 times less potent by the oral route. In the monkey, against dimaprit, AY-29,315 was 3 and 12 times more potent than ranitidine by the oral and i.v. routes, respectively. p.o./i.v. ratios indicate that, relative to ranitidine, the bioavailability of AY-29,315 by the oral route was low, particularly in the dog. In the dog, at 4 times the oral ED50 dose, the antisecretory effect of ranitidine lasted 190 +/- 3 min, while that of AY-29,315 lasted more than 9 h. AY-29,315 was 8 times more potent than ranitidine as an inhibitor of acetylsalicylic acid-induced ulcers in the rat.(ABSTRACT TRUNCATED AT 250 WORDS)     

Unequal opiate cross-tolerance to morphine in the locomotor-activation model in the mouse

Dose-response relationships for the opiate-induced stimulation of locomotion in mice were determined for etorphine, fentanyl, levorphanol, lofentanil and morphine, both before and after the subcutaneous implantation of a morphine pellet for 3 days. In non-tolerant mice, the relative potencies of these drugs compared to morphine paralleled those reported for other in vivo models of the actions of opiates. The most potent was lofentanil (ED50 = 3.8 micrograms/kg), which was approx. 6000 times more potent than morphine (ED50 = 24.2 mg/kg). A tolerance-induced 22-fold increase in the ED50 for morphine resulted in a similar cross-tolerance to levorphanol, but there was less cross-tolerance to fentanyl (4-fold), lofentanil (5-fold) and etorphine (7-fold). The smaller cross-tolerances of etorphine and lofentanil to morphine were not accompanied by changes in the levels of [3H]etorphine or [3H]lofentanil in brain, induced by morphine pellets, although the bound fraction of [3H]lofentanil in brain was slightly decreased (11-15%). The implications of the phenomenon of unequal cross-tolerance for the mechanism of tolerance at the opiate mu receptor are discussed.     

Synthesis and neuroleptic activity of 3-(1-substituted-4-piperidinyl)-1,2-benzisoxazoles

The synthesis of a series of 3-(1-substituted-4-piperidinyl)-1,2-benzisoxazoles is described. The neuroleptic activity of the series was evaluated by utilizing the climbing mice assay and inhibition of [3H]spiroperidol binding. Structure-activity relationships were studied by variation of the substituent on the benzisoxazole ring with concomitant variation of four different 1-piperidinyl substituents. Maximum neuroleptic activity was realized when there was a 6-fluoro substituent on the benzisoxazole ring. The 1-piperidinyl substituent appeared less significant, although in most cases, the (1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl group imparted maximum potency. The most potent compound in both assays was 6-fluoro-3-[1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) propyl]-4-piperidinyl]-1,2-benzisoxazole (11b).     

1,4-Dihydropyridines as antagonists of platelet activating factor. 1. Synthesis and structure-activity relationships of 2-(4-heterocyclyl)phenyl derivatives.

A novel class of 2-(4-heterocyclylphenyl)-1,4-dihydropyridines (2-38) possessing antagonist activity against platelet activating factor (PAF) was prepared by the Hantzsch synthesis from a variety of ethyl 4'-heterocyclic-substituted benzoylacetates, aryl or heteroaryl aldehydes, and substituted 3-aminocrotonamides or 3-aminocrotonate esters. Structure-activity relationships were evaluated where PAF antagonist activity was measured in vitro by determining the concentration of compound (IC50) required to inhibit the PAF-induced aggregation of rabbit washed platelets, and in vivo by determining the oral dose (ED50) which protected mice from a lethal injection of PAF. The nature of the substituent at the dihydropyridine 2-position was found to be important for both in vitro and in vivo activity, whereas there was greater flexibility for structural variation at the 4- and 5-positions. The most potent compound was 4-(2-chlorophenyl)-1,4-dihydro-3-(ethoxycarbonyl)-6-methyl-2-[4-(2- methylimidazo[4,5-c]pyrid-1-yl)phenyl]-5-[N-(2- pyridyl)carbamoyl]pyridine (17, UK-74,505), IC50 = 4.3 nM, ED50 = 0.26 mg/kg po, which was found to be approximately 33 times more potent in vitro (rabbit platelet aggregation) and about 8 times more potent in vivo (murine lethality) than WEB2086. Compound 17 also exhibited a long duration of action in the dog (inhibition of PAF-induced whole blood aggregation ex vivo was maintained for greater than 24 h following a single oral dose of 75 micrograms/kg) and was highly selective as a PAF antagonist, showing only weak affinity (IC50 = 6600 nM) for the [3H]nitrendipine binding site. As a result of its high oral potency, selectivity, and duration of action, UK-74,505 has been selected for clinical evaluation.     

强效镇痛剂研究——Ⅴ.N-[1-(β-羟基-β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺(7302)酯类衍生物的合成及镇痛活性

本文报道了一系列N-[1-(β-酰氧基-β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺类衍生物及其化学结构与镇痛强度之间的关系,并测定了几个代表化合物的镇痛作用时间及与阿片受体亲和力。实验结果表明,7302的β-羟基酯化后,均能维持一定的镇痛强度,其镇痛作用时间与母体化合物7302相近。从受体结合试验来看,酯化后与受体亲和的能力显著下降。