Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 27
Filter
Add more filters










Publication year range
1.
PDA J Pharm Sci Technol ; 50(4): 219-22, 1996.
Article in English | MEDLINE | ID: mdl-8810836

ABSTRACT

Mirfentanil hydrochloride, a novel CNS analgesic with a short duration of action, was successfully encapsulated in liposomes having a variety of compositions. The lipid composition of the formulation was varied to optimize the stabilization of liposomes and the encapsulation of solutes. Retention of mirfentanil hydrochloride was evaluated by storing loaded liposomes at several temperatures, and also after the physical stressing of formulations. High efficiency of drug encapsulation was observed in liposomes prepared using dipalmitoyl-L-alpha-phosphatidylcholine (DPPC) and the ternary mixture of dimyristoyl-L-alpha-phosphatidylcholine, cholesterol, and dicetyl phosphate (DMPC/CHOL/DCP), both with and without the further incorporation of monosialoganglioside (GM1). Only 35% of encapsulated drug was lost when the formulations containing GM1 were incubated with human plasma over a 24 hour period, suggesting that liposomal formulations containing GM1 could be used to control drug release in vivo.


Subject(s)
Analgesics/administration & dosage , Fentanyl/analogs & derivatives , Analgesics/blood , Analgesics/chemistry , Chemistry, Pharmaceutical , Delayed-Action Preparations , Drug Compounding , Drug Stability , Fentanyl/administration & dosage , Fentanyl/blood , Fentanyl/chemistry , Humans , In Vitro Techniques , Liposomes
2.
J Med Chem ; 33(10): 2876-82, 1990 Oct.
Article in English | MEDLINE | ID: mdl-2170652

ABSTRACT

The synthesis and intravenous analgesic activity of a series of 3-methyl-4-(N-phenyl amido)piperidines, entries 34-79, is described. The methoxyacetamide pharmacophore produced a series of compounds with optimal analgesic potency and short duration of action. cis-42 was 13,036 times more potent than morphine and 29 times more potent than fentanyl; however, the corresponding diastereomer 43 was only 2778 and 6 times more potent, respectively. Compounds 40, 43, 47, and 57 are extremely short acting; all had durations of action of about 2 min, which was about 1/5 of that of fentanyl in the mouse hot-plate test at a dose equivalent to 2 times the ED50 analgesic dose. Among the many compounds that displayed exceptional analgesic activity, duration of action was one of the main factors for choosing a candidate for further pharmacological investigation. At present, cis-1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-3-meth yl-4- [N-in equilibrium 2-fluorophenyl)methoxyacetamido]piperidine hydrochloride (40) (Anaquest, A-3331.HCl, Brifentanil) is in clinical evaluation. Opiate analgesics that possess short duration of action are excellent candidates for short surgical procedures in an outpatient setting where a rapid recovery is required.


Subject(s)
Analgesics/chemical synthesis , Piperidines/chemical synthesis , Tetrazoles/chemical synthesis , Analgesics/metabolism , Animals , Binding, Competitive , Chemical Phenomena , Chemistry, Physical , Dose-Response Relationship, Drug , Drug Design , Fentanyl/pharmacology , Mice , Morphine/pharmacology , Naloxone/metabolism , Piperidines/metabolism , Piperidines/pharmacology , Rats , Receptors, Opioid/metabolism , Tetrazoles/pharmacology , Time Factors
3.
J Med Chem ; 32(12): 2534-42, 1989 Dec.
Article in English | MEDLINE | ID: mdl-2585442

ABSTRACT

The incorporation of the 4-phenylpiperidine pharmacophore found in morphine into 4-anilidopiperidines related to fentanyl (1) led to a novel class of potent opioid analgesic and anesthetic agents with a favorable pharmacological profile. The synthesis, analgesic activity, and anesthetic properties of a series of 4-phenyl-4-anilidopiperidines (13-29) are discussed. Isosteric replacement of the phenyl by various heteroaryl substituents extended the series to include 4-heteroaryl-4-anilidopiperidines (30-53). Within this group, 1-[2-(1H-pyrazol-1-yl)ethyl]-4-(4-methylthiazol-2-yl)-4-(N- phenylpropionamido)piperidine (48), exhibited high analgesic potency, short duration of action, rapid recovery of motor coordination following anesthetic doses, and greater cardiovascular and respiratory safety during anesthesia as compared with opioids fentanyl (1) and alfentanil (2) currently in clinical use. Such analgesics could be of great utility to clinicians in the expanding outpatient surgical arena and for patient-controlled analgesia and computer assisted continuous infusion pain control techniques.


Subject(s)
Analgesics , Anesthetics , Anilides/pharmacology , Piperidines/pharmacology , Analgesics/chemical synthesis , Anesthetics/chemical synthesis , Anilides/chemical synthesis , Animals , Blood Gas Analysis , Chemical Phenomena , Chemistry , Crystallography , Hemodynamics/drug effects , Male , Mice , Motor Activity/drug effects , Piperidines/chemical synthesis , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Rats , Rats, Inbred Strains
4.
Anesth Analg ; 69(4): 450-6, 1989 Oct.
Article in English | MEDLINE | ID: mdl-2476953

ABSTRACT

The analgesic potency of pentamorphone, a 14-beta-aminomorphinone derivative, was compared to that of fentanyl and morphine by examining quantal dose-effect curves generated from data obtained in the mouse hot plate, rabbit tooth-pulp, and dog tail clamp tests. Onset and duration of antinociceptive effects were also compared. The ED50 values (mg/kg) were determined in mice for pentamorphone (0.0039), fentanyl (0.016), and morphine (7.3). In the rabbit tooth pulp test the ED50 values were 0.0009 mg/kg for pentamorphone, 0.0074 mg/kg for fentanyl, and 1.1 mg/kg for morphine; in the dog tail clamp test these values were 0.012 mg/kg for pentamorphone and 0.018 mg/kg for fentanyl. Duration of action (defined as the time until response to tooth pulp stimulation declined to 50% of maximum possible effect [MPE]) was 10 min with twice the IV ED50 for pentamorphone in mice. This duration was similar to that of the equipotent dose of fentanyl but much shorter than the duration of an equipotent potent dose of morphine (60 min). The duration in rabbits of the ED98 (IV) dose of pentamorphone was 65 min compared to 35 min for an equipotent dose of fentanyl and 200 min for morphine. Intramuscular doses of pentamorphone had significantly faster onset and shorter duration times than equipotent doses of morphine in both mice and rabbits. Pretreatment with naloxone in mice and rabbits attenuated the development of the antinociceptive effects of pentamorphone. This study shows that pentamorphone is a potent analgesic with a duration of action similar to that of fentanyl.


Subject(s)
Analgesics/pharmacology , Fentanyl/pharmacology , Hydromorphone/analogs & derivatives , Morphine/pharmacology , Nociceptors/drug effects , Animals , Dogs , Drug Evaluation, Preclinical , Female , Hydromorphone/pharmacology , Injections, Intramuscular , Injections, Intravenous , Male , Mice , Pain Measurement , Rabbits , Time Factors
5.
J Med Chem ; 32(5): 968-74, 1989 May.
Article in English | MEDLINE | ID: mdl-2709383

ABSTRACT

A new class of piperidine derivatives is added to the increasing family of compounds related to fentanyl and carfentanil. Herein, we describe the synthesis and pharmacology of a number of 1-(arylethyl)-4-(acylamino)-4-[(acyloxy)-methyl]piperidines such as 9, 15, and 23. As expected, many of these congeners of fentanyl are extremely potent narcotic agonists. The aim of the study was to identify short-acting analgesic agents (i.e. less than 6 min in the mouse hot-plate assay) for possible use in the surgical theater. Many of the drugs proved to be of intermediate and long duration (i.e. 6-15 min and greater than 15 min, respectively). In addition to analgesic activity, many of the compounds exhibited anesthetic properties as well. The structure-activity relationship for these entities is presented and discussed.


Subject(s)
Analgesics/chemical synthesis , Piperidines/chemical synthesis , Analgesics/pharmacology , Anesthetics/pharmacology , Animals , Male , Mice , Piperidines/pharmacology , Structure-Activity Relationship
6.
Anesth Analg ; 68(3): 194-200, 1989 Mar.
Article in English | MEDLINE | ID: mdl-2537587

ABSTRACT

This study was undertaken to evaluate the antinociceptive interactions of alpha 2 adrenergic and opiate receptors at the spinal level. Morphine and clonidine were administered intrathecally (i.t.) by lumbar puncture to rats either alone or in the presence of either i.t. yohimbine, an alpha 2 antagonist, or systemic naloxone, an opioid antagonist. The effect of tolerance to systematically administered morphine on responses to i.t. morphine and clonidine was examined in mice. Antinociception was determined by observing the response to a clamp applied to the tail (Haffner test) in mice and by the tail-flick test in rats; log dose-response curves for antinociception were generated for morphine, clonidine, and each drug combination. Morphine and clonidine both produced dose-dependent antinociception when given i.t. in both species. The i.t. administration of yohimbine attenuated the antinociceptive effect of both clonidine and morphine, but naloxone attenuated only the response to morphine. Further, a sub-analgetic dose of i.t. clonidine potentiated the effect of i.t. morphine. In morphine-tolerant mice, i.t. morphine was not efficacious whereas clonidine retained full efficacy, although potency was slightly diminished. Thus, it appears that alpha 2 adrenoceptor-mediated antinociception is independent of opiate receptor mechanisms. Clinical use of intrathecal combinations of alpha 2 adrenergic and opiate receptor agonists to increase analgesia and use of intrathecal alpha 2 agonists for pain relief in patients tolerant to opiates might deserve evaluation.


Subject(s)
Analgesia , Clonidine/administration & dosage , Morphine/administration & dosage , Receptors, Adrenergic, alpha/drug effects , Receptors, Opioid/drug effects , Spinal Cord/drug effects , Animals , Drug Interactions , Drug Tolerance , Male , Naloxone/pharmacology , Rats , Rats, Inbred Strains
7.
Anesth Analg ; 67(7): 616-24, 1988 Jul.
Article in English | MEDLINE | ID: mdl-2898220

ABSTRACT

This study was undertaken to compare the antinociceptive and behavioral effects of intrathecally administered opiates, alpha-2-adrenergic agonists, and local anesthetics injected by lumbar puncture in the mouse and rat. Antinociception was determined by observing the response to a clamp applied to the tail (Haffner test) of the mouse and by the rat tail-flick test; log dose-response curves for antinociception were generated for each drug in each test. Motor coordination and other behavioral effects were also observed. Morphine and fentanyl (mu-opiate agonists) as well as ethylketocyclazocine (EKC) and U50488H (kappa-opiate agonists), together with buprenorphine (partial mu-opiate agonist) and the alpha-2-adrenergic agonist clonidine, all produced antinociception in both species without causing significant behavioral or motor dysfunctions at antinociceptive doses. Xylazine (also an alpha-2-adrenergic agonist), ketamine, procaine, and lidocaine inhibited responses but only at doses that also produced motor impairment or paralysis. Nalbuphine (mixed opiate agonist-antagonist) was without any effect in both species. These data suggest that the mu- and kappa-opiate agonists and clonidine are the preferred agents for producing antinociception without compromising motor function.


Subject(s)
Adrenergic alpha-Agonists/administration & dosage , Analgesics, Opioid/administration & dosage , Analgesics , Anesthetics, Local/administration & dosage , Behavior, Animal/drug effects , Adrenergic alpha-Agonists/pharmacology , Analgesics, Opioid/pharmacology , Anesthetics, Local/pharmacology , Animals , Dose-Response Relationship, Drug , Injections, Spinal , Male , Mice , Mice, Inbred Strains , Pain Measurement , Rats , Rats, Inbred Strains
8.
Pharmacol Biochem Behav ; 30(1): 205-7, 1988 May.
Article in English | MEDLINE | ID: mdl-3051045

ABSTRACT

MK-801, a reported N-methyl-D-aspartate (NMDA) antagonist with affinity for the phencyclidine (PCP) receptor, injected intravenously in mice before a training trial in a passive avoidance procedure, produced a similar amnesic effect to that produced by the standard amnesic agent scopolamine. Compared to vehicle-treated mice, each drug produced significant amnesia, yet the potency of MK-801 was 40 times that of scopolamine. This result with the MK-801 is consistent with previous reports that drugs which act at PCP recognition sites within the brain produce memory impairing effects in rodents.


Subject(s)
Anticonvulsants/pharmacology , Dibenzocycloheptenes/pharmacology , Memory/drug effects , Animals , Dizocilpine Maleate , Dose-Response Relationship, Drug , Male , Mice , Reaction Time/drug effects , Scopolamine/pharmacology
9.
Life Sci ; 43(4): 365-72, 1988.
Article in English | MEDLINE | ID: mdl-3135460

ABSTRACT

The cardiovascular and respiratory effects of alfentanil in conscious freely moving rats, were evaluated after initial and subsequent injections. Doses of alfentanil (50, 130, 260, and 500 ug/kg) were given to naive rats (n = 4-5) and 1 hour later this dose was repeated. The resultant cardiovascular and respiratory effects were compared. At all doses there was a significant (p less than 0.05) depression of mean arterial pressure and heart rate after the initial dose of alfentanil. At doses of 50, 130, and 260 ug/kg, the second administration elicited significantly less depression of cardiovascular parameters than the initial dose. Maximum changes in respiratory parameters (PaCO2 and PaO2) were also significantly less after the second administration of alfentanil. This difference, in maximum respiratory depression, was not seen at the highest doses (500 ug/kg). These results indicate that tolerance, to the cardiorespiratory side effects seen after alfentanil, can occur in as little as 1 hour after subsequent bolus injections.


Subject(s)
Analgesics/pharmacology , Anesthetics/pharmacology , Blood Pressure/drug effects , Fentanyl/analogs & derivatives , Heart Rate/drug effects , Alfentanil , Analgesics/administration & dosage , Anesthetics/administration & dosage , Animals , Blood Gas Analysis , Carbon Dioxide/blood , Drug Tolerance , Fentanyl/administration & dosage , Fentanyl/pharmacology , Injections, Intravenous , Male , Oxygen/blood , Rats , Rats, Inbred Strains
10.
J Pharm Sci ; 74(1): 44-6, 1985 Jan.
Article in English | MEDLINE | ID: mdl-3981416

ABSTRACT

Several (3-aryl-2,3-dihydrobenzofuran-3-yl)alkanamines, designed as potential antidepressant agents with analgesic properties, were synthesized and pharmacologically evaluated. While two compounds (1a, 1f) displayed potent antitetrabenazine activity, concomitant antinociceptive activity in the phenylquinone writhing assay was not observed.


Subject(s)
Amines/chemical synthesis , Analgesics/chemical synthesis , Antidepressive Agents/chemical synthesis , Benzofurans/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Male , Mice , Tetrabenazine/antagonists & inhibitors
11.
J Med Chem ; 28(1): 66-73, 1985 Jan.
Article in English | MEDLINE | ID: mdl-3965715

ABSTRACT

An extensive series of 3-(1-indolinyl)benzylamines and related compounds was synthesized and tested for analgesic activity. After a detailed study of structure-activity relationships, 3-(1-indolinyl)benzylamine (2b) was selected for further investigation as the most interesting member of this novel class of compounds. It was active in both the phenylquinone writhing and tail-flick assays for analgesic activity. No motor deficits were observed in the rotorod test, and 2b was found to be free of any other effects on the central nervous system. The compound did not bind to opiate receptors, since it was inactive in inhibiting the stereospecific binding of [3H]naloxone in rat brain homogenates. Thus, 3-(1-indolinyl)benzylamine represents a novel analgesic with an unusual chemical structure and biological profile.


Subject(s)
Analgesics/chemical synthesis , Benzoquinones , Indoles/chemical synthesis , Animals , Binding, Competitive , Indoles/therapeutic use , Mice , Naloxone/metabolism , Pain/drug therapy , Quinones
12.
J Med Chem ; 27(3): 372-6, 1984 Mar.
Article in English | MEDLINE | ID: mdl-6607999

ABSTRACT

4,10-Dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetic acid (6) was previously reported as a potent antiinflammatory-analgesic agent characterized by an impressive therapeutic ratio in comparison with indomethacin. With the goal of finding compounds that might display even more favorable therapeutic ratios and/or enhanced antiinflammatory/analgesic properties in comparison to 6, we synthesized 4-(4,10-dihydro-10-oxothieno [3,2-c][1]-benzoxepin-8-yl) butanol (4b) and -butyric acid (5a) and a series of related derivatives. All compounds were evaluated for potential analgesic activity in the phenylquinone-induced writhing (PQW) assay, for antiinflammatory activity in the carrageenan-induced paw edema (CPE) model and, where warranted, for gastric irritation (GI) liability. Of the compounds investigated, 4b (HP 573) displays moderate analgesic-like activity in PQW, is approximately half as potent as indomethacin or 6 as an antiinflammatory agent in the CPE, and is characterized by an extremely low propensity to induce GI as reflected by comparison of the therapeutic ratios (GI ED50/CPE ED50: 4b greater than 46, 6 = 9.9, indomethacin = 0.4). Compound 4b was selected for clinical evaluation.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Benzoquinones , Benzoxepins/chemical synthesis , Butyrates/chemical synthesis , Animals , Benzoxepins/therapeutic use , Butyrates/therapeutic use , Edema/drug therapy , Male , Mice , Pain/drug therapy , Quinones , Rats , Rats, Inbred Strains
13.
J Med Chem ; 25(10): 1150-3, 1982 Oct.
Article in English | MEDLINE | ID: mdl-6128417

ABSTRACT

A series of [[(alkylamino)ethyl]thio]dibenz[b,f]thiepins (III) and their 10,11-dihydro derivatives (IV) was synthesized and subjected to broad analgesic/CNS screening. Preliminary results indicated a combination of analgesic/antidepressant profiles, similar to that observed for the [[(alkylamino)ethyl]thio]dibenz[b,f]oxepins (I) and their corresponding dihydro derivatives (II). The most active congener from the present series, 10b, shows an antinociceptive potency in the pentazocine range as assessed by phenyl-p-quinone-induced writhing (PQW) and tail flick in mice. It is also more than twice as active as imipramine in preventing tetrabenazine-induced ptosis (TBZ), a test widely recognized to be of predictive value for clinically efficacious antidepressants.


Subject(s)
Analgesics/chemical synthesis , Antidepressive Agents, Tricyclic/chemical synthesis , Benzoquinones , Dibenzothiepins/chemical synthesis , 5-Hydroxytryptophan/antagonists & inhibitors , Amphetamine/antagonists & inhibitors , Animals , Antipsychotic Agents/chemical synthesis , Apomorphine/antagonists & inhibitors , Blepharoptosis/prevention & control , Chemical Phenomena , Chemistry , Dibenzothiepins/pharmacology , Humans , Male , Quinones/antagonists & inhibitors , Rats , Stereotyped Behavior/drug effects
15.
J Med Chem ; 23(7): 726-9, 1980 Jul.
Article in English | MEDLINE | ID: mdl-6249930

ABSTRACT

A representative series of 5-(4-hydroxyphenyl)-2-azabicyclo[3.2.1]octanes was synthesized and evaluated in vitro, as well as in vivo, as potential analgetic agents. In general, moderate to good activity (19 twice as active as morphine) was observed in the phenylquinone writhing assay (PQW), while only marginal activity was detected by the tail-flick method. Compounds 19 and 18, being the most active in the PQW model, also demonstrated weak binding affinity for the opiate receptors labeled by [3H]naloxone in rat brain homogenates.


Subject(s)
Analgesics/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Bridged-Ring Compounds/chemical synthesis , Animals , Binding, Competitive , Brain/metabolism , Bridged Bicyclo Compounds/metabolism , Bridged Bicyclo Compounds/pharmacology , In Vitro Techniques , Male , Mice , Naloxone/metabolism , Rats , Receptors, Opioid/metabolism , Structure-Activity Relationship
16.
J Med Chem ; 23(5): 494-501, 1980 May.
Article in English | MEDLINE | ID: mdl-6103962

ABSTRACT

A series of [[(alkylamino)ethyl]thio]dibenz[b,f]oxepins (I) and their 10,11-dihydro derivatives (II) was synthesized and subjected to broad analgesic/CNS screening. Several analogues of both types, carrying small N-substituents and frequently a nuclear fluorine function, have been found to possess potent analgesic activity in the phenylquinone writhing assay (PQW) and the tail-flick test in mice. Many of these compounds also exhibited significant activity in antagonizing tetrabenazine-induced ptosis, as exemplified by 10b, 16b, and 18b. Results from the mouse jumping test indicated low physical dependence potential for these compounds, and further evidence for a nonnarcotic profile was provided by the absence of significant naloxone interactions with the tail-flick response. Compound 10b did not produce tolerance in mice following chronic administration in the PQW screen.


Subject(s)
Analgesics/chemical synthesis , Antidepressive Agents, Tricyclic/chemical synthesis , Dibenzoxepins/chemical synthesis , Amphetamine/antagonists & inhibitors , Amphetamine/toxicity , Animals , Anticonvulsants , Antipsychotic Agents , Chemical Phenomena , Chemistry , Dibenzoxepins/pharmacology , Mice
17.
Eur J Pharmacol ; 58(1): 19-25, 1979 Sep 01.
Article in English | MEDLINE | ID: mdl-499334

ABSTRACT

The activity of clonidine and its interaction with morphine was assessed in the mouse tail flick assay. In this assay, clonidine was found to be 10 times more potent than morphine. Clonidine potentiated morphine antinociceptive activity approximately five-fold and morphine potentiated clonidine activity four-fold. Clonidine's agonstic activity was not reversed by naloxone hydrochloride (10 mg/kg) while the potentiating effect of clonidine by morphine was. Tolerance to the antinociceptive effect of morphine was observed in morphine pellet-implanted mice but no cross tolerance was observed for clonidine. These data indicate that clonidine-induced analgesia is not a result of an interaction at morphine receptors; but rather, common pathway(s) are present which appear to complement the agonistic interaction of each.


Subject(s)
Analgesics , Clonidine/pharmacology , Morphine/pharmacology , Animals , Dose-Response Relationship, Drug , Drug Synergism , Drug Tolerance , Male , Mice , Naloxone/pharmacology , Reaction Time/drug effects
18.
J Med Chem ; 22(7): 834-9, 1979 Jul.
Article in English | MEDLINE | ID: mdl-448682

ABSTRACT

A series of 10,11-dihydro-11-oxospiro[dibenz[b,f]oxepin-10,4'-piperdine] derivatives (II) was synthesized and evaluated for analgesic activity in the phenylquinone writhing assay (PQW) and the tail-flick test in mice. Preliminary structure-activity correlations indicate that optimum activity is associated with a short-chain (R less than or equal to C2) N substituent and a nuclear fluorine function, as exemplified by 9b. This compound, when administered orally, was equipotent to morphine in protecting against mouse writhing. The observation that the PQW activity of 9b remained relatively unchanged after naloxone challenge seems to favor a nonnarcotic profile.


Subject(s)
Analgesics/chemical synthesis , Dibenzoxepins/chemical synthesis , Animals , Dibenzoxepins/pharmacology , Dose-Response Relationship, Drug , Male , Methods , Mice , Postural Balance/drug effects , Quinones/antagonists & inhibitors , Reaction Time/drug effects , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...