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At least 19 recordsLinked to original sources
PubMed1986

Probes for narcotic receptor mediated phenomena. 9. Synthesis of (+/-)-(3 alpha,6a alpha,11a beta)-1,3,4,5,6,11a-hexahydro-2-methyl-2H-3,6a- methanobenzofuro[2,3-c]azocin-10-ol, an oxide-bridged 5-(m-hydroxyphenyl)morphan.

The synthesis of racemic (3 alpha,6a alpha,11a beta)-1,3,4,5,6,11a- hexahydro-2-methyl-2H-3,6a-methanobenzofuro[2,3-c]azocin -10-ol (2d) is described. The route used acid-catalyzed ring closure of enamine 5 to yield the unsaturated phenylmorphan 6. Conversion of 6 to oxide-bridged 2d was accomplished in a multistep fashion that utilized the introduction of a bromine atom, followed by O-demethylation of the phenolic methyl ethers and base-catalyzed intramolecular phenoxide displacement of the bromine. Compound (+/-)-2d represents an oxide-bridged derivative of the potent 5-(m-hydroxyphenyl)morphan class of opioid analgesics 1. Unlike the 5-(m-hydroxyphenyl)morphans that have a freely rotating phenyl group, 2d has the phenyl ring conformationally restricted at an angle of 49 degrees relative to atoms 1, 3, 11a, and 12 of 2d. The low binding of (+/-)-2d to rat brain homogenate receptor preparations [IC50 = 1000 nM] may indicate that the phenyl angle of 49 degrees is not suitable for binding to opioid receptors.

Animals↗
PubMed1976

Selective alpha-adrenoceptor blocking actions of a new derivative of 2-halogenotheylamine: 6-(2-bromoethyl)-10,11-methylenedioxy-5,6,7,8-tetrahydrodibenz[c,e]azocine.

A new compound, 6-(2-bromoethyl)-10,11-methylenedioxy-5,6,7,8-tetrahydrodibenz [c,e] azocine (DA-VIII-MBr) was found to have a more selective alpha-adrenergic blocking action than dibenamine or phenoxybenzamine. From dose-response curves for adrenaline and 5-hydroxytryptamine (5-HT) obtained in strips of rat aorta before and after incubation with each of the three blocking agents, the fractions of receptors remaining active for adrenaline and 5-HT, respectively, were estimated. After blockade with DA-VIII-MBr the receptors for adrenaline were blocked considerably, but those for 5-HT were little affected. Dibenamine blocked the receptors to adrenaline and 5-HT almost equally. The effective dose of phenoxybenzamine for adrenaline receptors was less than one hundredth that of dibenamine or DA-VIII-MBr, but specificity for these receptors was intermediate between those of dibenamine and DA-VIII-MBr. The structure of DA-VIII-MBr is an analog of apogalanthamine and its nitrogen atom bears the 2-halogenoethylamine group in part of an eight membered ring.

Adrenergic alpha-Antagonists↗
PubMed1977

Synthesis of certain 4-oxo-1.2.3.4-tetrahydroquinoline and benzazocine derivatives likely to possess analgesic activity.

Cyanoethylation of anthranilic acid afforded the N-cyanoethyl derivative which on treatment with ethanolic and methanolic hydrogen chloride yielded the corresponding diethyl and dimethyl esters respectively. Application of the Dieckmann's conditions to the N-acetyl derivatives of the two esters using sodium hydride and sodium ethoxide afforded different products. With the former, the expected products were obtained, while with the latter catalyst both esters furnished one and the same compound which was shown to be a benzazocine trione. The structure of the azocine was inferred from elemental analysis, spectroscopic data and formation of derivatives.

Analgesics↗
PubMed1985

Alpha-adrenolytic properties of apogalanthamine and azapetine analogs.

Selectivities were examined between alpha 1 and alpha 2-adrenolytic activities of two apogalanthamine analogs (dibenzazocine derivatives), 6-methyl-5,6,7,8-tetrahydrodibenz[c,e]-azocine (DA-VIII-Me) and its N-allyl analog (DA-VIII-allyl), and two dibenzazepine derivatives, azapetine (DA-VII-allyl) and its N-methyl analog (DA-VII-Me). The alpha-adrenolytic activities were evaluated as inhibitory effects against the response to norepinephrine of isolated vas deferens and anococcygeus muscle of rats. The pA2 values for DA-VIII-Me, DA-VIII-allyl, DA-VII-Me and azapetine on the isolated rat vas deferens were 7.32, 7.76. 6.61 and 7.78 respectively, which were similar to those on the anococcygeus muscle. The alpha 2-adrenolytic activities of these compounds against the twitch-inhibitory response to clonidine in transmurally stimulated rat vas deferens and guinea-pig ileum were less potent than those against the above alpha 1-adrenoceptors. In addition, their inhibitory activities on the aggregation of human platelets induced by norepinephrine were weaker than those of phentolamine and yohimbine. These results indicate that the apogalanthamine and azapetine analogs tested are more selective in blocking alpha 1-adrenoceptors than alpha 2-adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1989

Tonazocine mesylate in postoperative pain patients: a double-blind placebo controlled analgesic study.

One hundred-fifty post-operative adult patients with moderate to severe pain were enrolled into this analgesic efficacy study comparing single doses of tonazocine mesylate, a new mixed agonist-antagonist opioid analgesic, with morphine. The patients were randomly assigned to five treatment groups: tonazocine mesylate 2, 4, 8 mg; morphine sulfate 10 mg and a placebo group. The results showed mean total pain relief scores for tonazocine 4 mg were nearly identical with that of morphine sulfate 10 mg while 8 mg of tonazocine were superior to 10 mg of morphine. All the active medication groups were superior to the placebo group (P less than 0.02) for both pain intensity and pain relief. Relative potency determined by the dose response indicates that 3.2 mg of tonazocine is equivalent to 10 mg of morphine. Drowsiness was the main adverse reaction seen in all active treatment groups. Tonazocine mesylate appears to be a potent analgesic with promising clinical usefulness and warrants further study.

Adolescent↗
PubMed1992

Enantioselectivity of asocainol studied at different conditions: a novel approach to check the feasibility of molecular models of antiarrhythmic drug action.

In terms of the "guarded receptor" hypothesis, changes in potency of Na+ channel blocking drugs reflect alterations in drug access to and/or egress from a compartment facing a binding site with constant affinity. Potency is therefore assumed to be determined by changes in drug diffusion, its mobility in the electric field, protonation etc. Hence, the potencies of enantiomers, i.e. compounds with identical physicochemical properties, should be influenced in a parallel manner by the condition. To test this prediction, actions of the enantiomers of the stereoselective antiarrhythmic drug asocainol were compared at various membrane potentials and stimulus frequencies. Several experimental models indicative of Na+ channel block were used: the elevation of the rectangular pulse stimulation threshold (RPT) and the suppression of alternating-current induced arrhythmia (ACT) were studied in guinea-pig atria. The reduction of the upstroke velocity of action potentials was measured in guinea-pig papillary muscles. The inhibition of whole-cell Na+ currents was investigated in isolated guinea-pig ventricular myocytes. In all these assays, (+)-asocainol was more potent than the (-)-enantiomer. Lowering the membrane potential and/or increasing the stimulus frequency enhanced the effects of both enantiomers. However, over a certain range of conditions, the potency of (+)-asocainol was more markedly affected than that of (-)-asocainol, indicating that the eudismic ratio between potencies of the two drugs is not constant. Accordingly, these findings are inconsistent with the guarded receptor hypothesis.

Action Potentials↗
PubMed1988

Cue properties of oral and transdermal nicotine in the rat.

In a standard two-lever drug discrimination paradigm, rats were trained to discriminate nicotine 0.5 mg/kg PO from saline. Injections occurred 15 min before the session. Subjects reached the training criterion in a mean of 38 sessions. Nicotine PO, SC, and IP generated similar dose-effect curves (ED50 = 0.073 mg/kg PO, 0.076 mg/kg SC, 0.090 mg/kg IP); the dose-effect curve for transdermal (TD) administration fell approximately 1 log unit to the right (ED50 = 1.34 mg/kg). The percentage of rats choosing the nicotine-appropriate lever peaked at 15 min and gradually decreased to 50% or less by 180 min for nicotine PO and TD, a time-decay function similar to that previously shown for SC administration. The nicotinic cholinergic agonist cytisine (0.5-8.0 mg/kg) PO and TD produced up to 56% nicotine-appropriate responding, while the muscarinic cholinergic agonist arecoline (1.0-4.0 mg/kg) PO and TD produced only saline-appropriate responding. The nicotine cue did not generalize to the cholinergic antagonist mecamylamine (0.125-0.5 mg/kg) PO or TD; mecamylamine 0.5 mg/kg PO but not TD completely blocked the PO and TD nicotine cues. These results show that an approximately equal cue occurs with PO, IP, and SC administration, and that the TD cue is considerably weaker. The significance of the procedure as an animal analog of human transdermal nicotine intake is discussed.

Administration, Cutaneous↗
PubMed1992

Kappa opioid agonists inhibit transmitter release from guinea pig hippocampal mossy fiber synaptosomes.

Opioid agonists specific for the mu, delta, and kappa opioid receptor subtypes were tested for their ability to modulate potassium-evoked release of L-glutamate and dynorphin B-like immunoreactivity from guinea pig hippocampal mossy fiber synaptosomes. The kappa opioid agonists U-62,066E and (-) ethylketocyclazocine, but not the mu agonist [D-Ala2,N-MePhe4,Gly5-ol]-enkephalin (DAGO) nor the delta agonist [D-Pen2,5]enkephalin (DPDE), inhibited the potassium-evoked release of L-glutamate and dynorphin B-like immunoreactivity. U-62,066E, but not DAGO or DPDE, also inhibited the potassium-evoked rise in mossy fiber synaptosomal cytosolic Ca2+ levels, indicating a possible mechanism for kappa agonist inhibition of transmitter release. DAGO and DPDE were found to be without any effect on cytosolic Ca2+ levels or transmitter release in this preparation. The U-62,066E inhibition of the potassium-evoked rise in synaptosomal cytosolic Ca2+ levels was partially attenuated by the opioid antagonist quadazocine and insensitive to the delta-opioid specific antagonist ICI 174,864 and the mu opioid-preferring antagonists naloxone and naltrexone. Quadazocine also reversed U-62,066E inhibition of the potassium-evoked release of L-glutamate, but not dynorphin B-like immunoreactivity. These results suggest that kappa opioid agonists inhibit transmitter release from mossy fiber terminals through both kappa opioid and non-kappa opioid receptor mediated mechanisms.

Animals↗
PubMed1990

Behavioral effects after intrathecal administration of cholinergic receptor agonists in the rat.

Behavioral effects of nicotine and cytisine, and the cholinesterase inhibitors physostigmine and 9-amino-1,2,3,4-tetrahydroacridine (THA), administered intrathecally (IT) at the lumbar level in the rat have been evaluated. Antinociceptive dose relationships were established using the tail immersion test. Total activity, locomotion and rearing were also measured in computerized test boxes. The nicotinic receptor antagonist, mecamylamine, and the muscarinic receptor antagonist, atropine, were used to study the selectivity of the effects. Physostigmine and THA significantly decreased total activity, locomotion and rearing as compared to control animals. The motor effects of physostigmine were completely antagonized only partly. Mecamylamine had no antagonistic effect. Nicotine did not affect any activity parameter. Cytisin reduced total activity and locomotion 1-6 min after dose. IT physostigmine, 15 micrograms, increased tail immersion latency for 30 min. No significant increase in response latency in this test was observed after the IT administration of nicotine or THA, whereas cytisine elicited a small increase. The IT administration of THA, nicotine and cytisine was also associated with gnawing, vocalization and hyperactivity and in the case of THA, diarrhoea. These effects were blocked by mecamylamine. Physostigmine antinociception as well as the behavioral effects including total activity, locomotion and rearing caused by physostigmine and by THA are most probably due to an action on spinal muscarinic receptors. Nicotinic receptors do not seem to be involved in spinal antinociception. Some aversive behavioral effects caused by the IT administration of nicotinic receptor agonists could, however, be attenuated by the spinal administration of the antagonist mecamylamine, which may indicate the involvement of nicotinic receptors in afferent sensory transmission.

Alkaloids↗
PubMed1990

Molecular pharmacological aspects of antiarrhythmic activity. I. Class I and class III compounds and lipid peroxidation.

The effect of nineteen antiarrhythmic agents on nonenzymatic lipid peroxidation, using rat hepatic microsomes, was studied. Lipid peroxidation was induced by Fe2(+)-ascorbic acid and assayed spectrophotometrically by measuring the 2-thiobarbituric acid reactive material. The compounds tested have various structural characteristics and represent class I and III of antiarrhythmics as classified by Vaughan Williams. The RM values, derived from reversed-phase thin-layer chromatography, were determined, and sigma f values calculated in order to correlate lipophilicity and antioxidant activity. The antiarrhythmics studied inhibited lipid peroxidation to various degrees. No apparent structural factor could definitely be attributed to this effect and antioxidants are found among both class I and class III compounds. There is a trend toward a parabolic relationship between antioxidant potency and lipophilicity. Three of the tested antiarrhythmics, namely the lipophilic amiodarone, aprindine and asocainol, were very potent antioxidants, and a further investigation of concentration and time dependency of lipid peroxidation was performed. It is suggested that, at least for some antiarrhythmic drugs, antioxidant activity may be part of their mode of action, and that it may form an additional beneficial feature for the treatment of cardiac failure.

Amiodarone↗
PubMed1988

[3H](-)nicotine binding sites in fetal human brain.

The development of putative nicotinic binding sites in brains from human fetuses of 12-19 weeks gestation was studied. The binding of [3H](-)nicotine to fetal human brain membranes, using a rapid filtration method, was saturable and stereospecific. Scatchard analysis revealed a single class of high affinity sites with a Kd of 1.5 +/- 0.5 nM and a Bmax of 4.5 +/- 1.9 fmol/mg protein (n = 11). [3H](-)nicotine binding increased between the ages of 12 and 19 weeks in human fetal brain (r = 0.63, n = 20, P less than 0.01). In competition studies nicotinic agonists were the most effective in inhibiting [3H](-)nicotine binding whereas antagonists were relatively ineffective. Ki values for displacing ligands in the presence of [3H](-)nicotine were: cytisine, 1.6 nM; (-)nicotine, 16 nM; (+) nicotine, 510 nM; dihydro-beta-erythroidine, 1.9 microM; dimethyl-4-phenylpiperazinium, 6.5 microM; choline chloride, 25 microM. Atropine and alpha-bungarotoxin failed to inhibit binding up to 50 microM. Comparison of dissected brain regions revealed regional variations in the density of nicotinic binding sites: specific binding of [3H](-)nicotine was greatest in the nucleus basalis of Meynert, globus pallidus, caudate-putamen and thalamus, and lowest in the medulla. These results are interpreted in relation to the development of functional cholinergic transmission in human fetal brain, and the potential vulnerability of this system to maternal tobacco usage.

Alkaloids↗
PubMed1990

Kappa opioid receptor-mediated depression of activity evoked in convergent dorsal horn cells by thermal and non-thermal noxious stimulation.

The response of convergent dorsal horn cells to tonic and phasic noxious heating and to noxious pinching was studied before and after topical application of a solution (30 nmol) of the kappa agonist U-50,488H to the dorsal surface of the spinal cord. U-50,488H depressed the discharge of convergent units evoked by thermal and mechanical nociceptive stimuli. The opiate antagonist WIN 44,441-3 reversed the effect of U-50,488H. It is concluded that kappa opioids are effective in preventing the depolarization of convergent dorsal horn neurons evoked by either thermal or non-thermal noxious stimuli.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗