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At least 19 recordsLinked to original sources
PubMed1980

Aporphines. 31. Synthesis and antitumor activity of aporphine nitrogen mustards.

A series of aporphine nitrogen mustards and their congeners (1b-g) has been prepared. N-[[Bis(2-chloroethyl)-amino]-2,11-dihyroxy-10-methoxynoraporphine (1b) and its mono- and diacetyl ester derivatives (1c-d) were prepared from N-(chloroacetyl)-2,11-diacetoxy-10-methoxynoraporphine (2). Reaction of 2 with diethanolamine under various conditions and different solvents resulted in the corresponding N-[[bis(2-hydroxyethyl)amino]acetyl] precursors, which were subsequently treated with SOCl2 to yield the target compounds. N-(2-Choroethyl)norapocodeine (1e) was obtained from the chlorination of N-(2-hydroxyethyl)norapocodeine (9) with SOCl2. Prolonging such treatment was found to result in the formation of N-[2-(chloroethoxy)ethyl]norapocodeine (1f) at the expense of 1e. N-[[[N'-(2-Chloroethyl)carbamyl]oxy]ethyl]norapocodeine (1g) and its 11-(2-chloroethyl)carbamyl derivative (1h) were also prepared. All the double-armed aporphine amide nitrogen mustards (ab-d) were found to have antitumor activity. The single-armed aporphine nitrogen mustard (1e) was also active in P388 but the activity was less than that observed with 1b-d. The lead compound 1a was inactive in the LE1210 and P388 systems at the doses tested. Similarly, the two aporphine mustard congeners (1f,g) were also inactive in the P388 system. All the activity was observed in the intraperitoneally innoculated tumor systems.

Animals↗
PubMed1977

Aporphines, 21. (1,2) Dopaminergic activity of aporphine and benzylisoquinoline derivatives. Synthesis of 8-hydroxyaporphines and 1-(hydroxybenzyl)-2-n-propyl-1,2,3,4-tetrahydroisoquinolines.

The synthesis and physical properties of 8-hydroxyaporphine (3a) and 8-hydroxy-N-n-propylnoraporphine (3b) are described. The replacement of the rigid aporphine ring system by the more flexible benzyltetrahydroisoquinoline moiety, still containing all the necessary substitutents of the potent dopamine agonist N-n-propylnorapomorphine (1b) (NPA), resulted in the synthesis of 1-(3,4-dihydroxybenzyl)-2-propyl-1,2,3,4-tetrahydroisoquinoline (4). Analogous to 4,1-(4-hydroxybenzyl)-2-propyl-1,2,3,4-tetrahydroisoquinoline (5) was synthesized for a direct comparison with the biological activity of the corresponding 10-hydroxyaporphine (2). All compounds synthesized were evaluated as salts of their racemates. In animals with unilateral 6-OHDA lesion of the nigrostriatal pathway, (-)NPA and 2 caused dose-dependent contralateral circling behavior although activity was greatly reduced for the monohydroxylated aporphine 2. 3b,4, and 5 were inactive at doses of 0.25-4.0 mg/kg sc. Compounds 2 and 3b exhibited very weak activity in the stereotype tests in comparison to the response obtained with apomorphine and (-)-NPA. 4 and 5 failed to induce any sterotyped response. These compounds were also investigated for their ability to stimulate locomotor activity following direct injection into the nucleus accumbens. (-)-NPA induced a modest increase in activity but apomorphine completely failed to elicit a locomotor responses and antagonized the effect induced by dopamine. 2,3b, 4 and 5 neither enhanced locomotor activity on direct injection into the nucleus accumbens nor antagonized the hyperactivity response to intraacumbens dopamine when administered peripherally. On direct injection into the caudate-putamen only apomorphine induced stereotyped biting; (-)-NPA, 2, 3b, 4, and 5 were inactive. The differential activity of the aporphine derivatives in these tests strongly supports the possible existence of different types of dopamine receptors within the extrapyramidal and mesolimbic systems. The present studies confirm that the flexible benzylisoquinolines 4 and 5 do not adopt the active dopamine conformation and that the rigid aporphines, preferably containing hydroxyl functions at the 10 or 11 positions, are of greater importance in eliciting potent dopamine agonist activity.

Animals↗
PubMed1981

Aporphines, 36. Dopamine receptor interactions of trihydroxyaporphines. Synthesis, radioreceptor binding, and striatal adenylate cyclase stimulation of 2,10,11-trihydroxyaporphines in comparison with other hydroxylated aporphines.

The presence of the A ring of aporphines and the addition of substituents to it and to other portions of the aporphine ring systems can extend explorations of the dimensions and other characteristics of the dopamine receptors. Accordingly, the synthesis and some physical and pharmacological properties of a series of (-)-2,10,11-trihydroxyaporphines (3a-g) are described. Structure-activity relationships among mono-, di-, and trihydroxyaporphines were evaluated against the high-affinity (nanomolar) binding of [3H]apomorphine (APO) and [3H]spiroperidol (SPR) with a subcellular fraction (P4) of caudate nucleus from bovine brain. In addition, DA-sensitive adenylate cyclase activity was evaluated in homogenates of rat brain striatal tissue. The rank order of displacement of [3H]APO by potent aporphines (IC50 less than or equal to 30 nM) correlated approximately with their ability to stimulate cyclic AMP synthesis. Potency orders against two ligands were dissimilar; for example, increasing the size of N6-alkyl substituents increased potency vs. [3H]SPR but not vs. [3H]APO binding. Moreover, [3H]SPR binding correlated poorly with cyclase activity or [3H]APO binding, suggesting a closer relationship of [3H]APO binding to dopamine-sensitive adenylate cyclase activity.

Adenylyl Cyclases↗
PubMed1993

Preparation and pharmacological evaluation of enantiomers of certain nonoxygenated aporphines: (+)- and (-)-aporphine and (+)- and (-)-10-methylaporphine.

The subject compounds were prepared as a part of a continuing structure-activity study of the contrasting actions (agonism-antagonism) of (+)- and (-)-11-hydroxy-10-methylaporphine at serotonin (5-HT1A) receptors. None of the targeted nonoxygenated aporphine derivatives demonstrated significant activity in assays for any effects at serotonin 5-HT1A receptors. It is concluded that, in the aporphine series, serotonergic agonist or antagonism requires an alkyl group ortho to a phenolic OH group in the A ring.

Animals↗
PubMed1976

Aporphines. 14 Dopaminergic and antinociceptive activity of aporphine derivatives. Synthesis of 10-hydroxyaporphines and 10-hydroxy-N-n-propylnoraporphine.

The synthesis of racemic 10-hydroxyaporphine [(+/-)-2a] and 10-hydroxy-N-n-propylnoraporphine [(+/)-2b] is described. The method involved a Reissert alkylation-Pschorr cyclization route. The dopaminergic activity of (+/-)-2b was evaluated in comparison with L-Dopa, (-)-apomorphine (1a), (+/-)-N-n-propylnorapomorphine (NPA) (1b), and (+/-)-11-hydroxy-N-n-propylnoraporphine [(+/-)-11-OH-PNA] by the behavioral model of rotational behavior in animals after unilateral lesion of the ascending DA pathways. The dopaminergic activity of NPA and 11-OH-PNA is essentially equivalent to L-Dopa and (-)-apomorphine, and both are more active than (+/-)-2b. Furthermore, (+/-)-NPA (threshold doses, 5 mug/kg) appears to be even more potent that (-)-apomorphine (threshold doses, 25 mug/kg). The duration of action of NPA and 11-OH-PNA is considerably longer than that obtained with L-Dopa. The antinociceptive activity of (+/-)-2b was evaluated by the tail-flick procedure and compared with 1a, 2b, morphine, and L-Dopa. Weak but significant antinociceptive activity was shown by (+/-)-2b and by (+/-)-1b but not by (-)-apomorphine. This effect was not antagonized by naloxone. The finding that (+/-)-2b and particularly (+/-)-11-OH-PNA are active in doses from 500 to 50 mug/kg, respectively, in causing rotational behavior further supports previous studies indicating that N-n-propyl derivatives of monohydroxylated aporphines were more active than the corresponding parent N-methyl derivatives as DA receptor agonists and that a catechol system is not an absolute requirement for dopaminergic activity in such aporphines.

Analgesics↗
PubMed1979

Aporphines. 25-trimethylislyl derivatives of N-methyl and N-propyl aporphines: gas chromatographic and mass spectrometric properties.

A series of synthetic, semisynthetic and naturally occurring aporphine alkaloids were converted to the O-trimethylsilyl derivatives, and analyzed by gas chromatography mass spectrometry. A discussion of structurally informative fragment ions along with gas chromatographic data is presented. Their applicability to the analysis of biological metabolites of apomorphine, a CNS active structural analog of dopamine, is discussed.

Apomorphine↗
PubMed1976

Aporphines. 15. Action of aporphine alkaloids on dopaminergic mechanisms in rat brain.

Of eleven aporphine analogues tested on striatal adenylate cyclase only (-)-apomorphine and (+/-)-N-n-propyl-norapomorphine (+/-(NPA)) were effective in stimulating the cyclase from rat brain. Inactive compounds included (+/-)-isoapomorphine, (-)-1,2-dihydroxyaporphine and (+/-)-10-hydroxy-N-n-propylnoraporphine. (+)-Bulbocapnine was an effective antagonist of the stimulating effects of dopamine or (-)-apomorphine on striatal adenylate cyclase. Injection of (-)-apomorphine into the lateral ventricle of rats with unilateral 6-hydroxydopamine-induced lesions of the nigro-striatal pathway caused the animals to rotate away from the side of the lesion. Intraventricular injection of 25 mug (+/-)-10-hydroxy-N-n-propylnorapomorphine was ineffective in producing rotation. The results are discussed in relation to the structural requirements for CNS dopamine receptor agonists.

Adenylyl Cyclases↗
PubMed1976

Aporphines. 16. Action of aporphine alkaloids on locomotor activity in rats with 6-hydroxydopamine lesions of the nucleus accumbens.

(-)-Apomorphine and (+/-)-N-n-propylnorapomorphine (+/-)-NPA) produce stereotypy but not locomotor activity in normal rats. In rats with selective bilateral lesions of dopamine terminals in the nucleus accumbens induced by microinjection of 6-hydroxydopamine both compounds produced a marked stimulation of locomotor activity. (+/-)-NPA was considerably more potent than (-) -apomorphine. The maximal intensity of stimulation produced by the two drugs was, however, similar. The locomotor stimulant effects of (-)-apomorphine were inhibited by (+)-bulbocapnine (20 mg/kg) or pimozide (0.5 mg/kg). (+/-)-N-n-Propylnorapocodeine also produced a long-lasting stimulation of locomotor activity. (+/-)-Aporphine, (+/-)-isopomorphine, (-)-1,2-dihydroxyaporphine, and (-)-nuciferine were all inactive in stimulating locomotor activity.

Animals↗
PubMed1981

Aporphines. 34. (-)-2,10,11-Trihydroxy-N-n-propylnoraporphine, a novel dopaminergic aporphine alkaloid with anticonvulsant activity.

(-)-2,10,11-Trihydroxy-N-n-propylnoraporphine (TNPA,2c) has been synthesized from thebaine (3a), via northebaine (3b), normorphothebaine (2a), and alkylation to the N-propyl derivative 2b. O-Demethylation gave the desired product 2c. Compound 2c showed activity comparable to its 10,11-dihyroxy counterpart (NPA, 1b) on the stimulation of dopamine-sensitive adenylate cyclase in carp retinal homogenates. The evaluation of 2c on audiogenic seizures in mice, in the protection against paroxysimal EEG and myoclonic response to photic stimulation in the baboon, revealed a similar pharmacological profile in comparison to NPA and apomorphine, with TNPA showing a prolonged duration of action in abolishing myoclonic response to photic stimulation in the baboon.

Acoustic Stimulation↗
PubMed1990

Aporphines as antagonists of dopamine D-1 receptors.

The aporphine alkaloids are a class of compounds known to possess activity at both D-1 and D-2 dopamine receptors. (R)-Apomorphine and (S)-bulbocapnine are examples of compounds which have agonist and antagonist activity, respectively, at D-1 receptors. A series of optically pure aporphines was synthesized and their activity at D-1 and D-2 dopamine receptors was studied. The (R)-aporphines uniformly had greater affinity for both D-1 and D-2 receptors than their S antipodes. Dihydroxy compound (R)-apomorphine, in accord with previous studies, was found to be a D-1 agonist. Aporphines possessing a single hydroxy group at C-11 are antagonists at the D-1 receptor. The corresponding methoxy compounds are virtually inactive at dopamine receptors. The most potent compounds, (R)-11-hydroxyaporphine (R-14) and (R)-10-bromo-11-hydroxyaporphine (R-26), are more potent than bulbocapnine as D-1 antagonists but are not as selective. A model for binding of aporphines to the D-1 receptor was formulated in which binding interactions between the receptor and the basic nitrogen and the C-11 hydroxy group of the aporphine are required for high-affinity binding to the receptor. The absolute configuration at C-6a determines the orientation of the N-6 lone pair and binding is optimal for the 6aR series. The agonist or antagonist activity of an aporphine is determined by the presence or absence, respectively, of a hydroxy group at C-10. A hydrophobic binding site may be present and may account for the high antagonist activity of (S)-bulbocapnine.

Adenylyl Cyclases↗
PubMedDate not supplied

Neuroleptic-like, anticonvulsant and antinociceptive effects of aporphine alkaloids: bulbocapnine, corytuberine, boldine and glaucine.

The aporphine alkaloids bulbocapnine, corytuberine, boldine and glaucine were studied in mice and compared with haloperidol, phenobarbital and morphine. All aporphines inhibited the exploratory rearing activity and elicited palpebral ptosis, catalepsy, hypothermia, and prolonged anesthesia by thiopental. They also reduced nociception (hot plate; phenylquinone-induced writhing) and (except for corytuberine) were anticonvulsant against harman and picrotoxin, but not against bicuculline and pentetrazol; corytuberine was proconvulsant. The aporphines (except for corytuberine) antagonized the apomorphine- and methylphenidate-induced stereotyped gnawing and also the apomorphine-induced climbing activity; corytuberine was prostereotypic. The antignawing effects (including those of haloperidol) were stronger when the antagonists were administered after the agonists (gnawing full-fletched) rather than before them: this led to the speculation of a metaphilic interaction at central site(s). Clonazepam inhibited the antistereotypic effect (vs apomorphine) more potently with the aporphines than with haloperidol. The antinociceptive effect (writhing) of the aporphines was, in contrast to that of morphine, resistant to both naloxone and yohimbine. The latter applied also to the antilicking action in the hot plate test; the antijumping effect of boldine was (like that of morphine) antagonized by both yohimbine and naloxone, whereas that of corytuberine was inhibited only by naloxone and that of bulbocapnine preferentially by yohimbine. Hence, opioid and adrenergic mechanisms are unequally involved in the antinociceptive effects of the aporphines. The present results also showed that licking and jumping (in the hot plate test) are pharmacologically different phenomena. In low doses, the aporphines and haloperidol antagonized the antinociceptive effect of morphine (hot plate); hence, these drugs may be considered partial agonists or partial antagonists, respectively.

Analgesics↗
PubMed2004

Alkaloids from Cassytha filiformis and related aporphines: antitrypanosomal activity, cytotoxicity, and interaction with DNA and topoisomerases.

Cassytha filiformis (Lauraceae), a widely distributed parasitic plant, contains several aporphine alkaloids and is often used in African folk medicine to treat cancer, African trypanosomiasis and other diseases. In a previous investigation, we showed that the alkaloid plant extract and the isolated aporphines possessed in vitro cytotoxic properties. In this paper, we evaluated the in vitro activity of the alkaloid extract (IC50 = 2.2 microg/mL) and its three major aporphine alkaloids (actinodaphnine, cassythine, and dicentrine) on Trypanosoma brucei brucei as well as four related commercially available aporphines (bulbocapnine, glaucine, isocorydine, boldine). Only the three alkaloids from Cassytha filiformis were active on the trypanosomes in vitro (IC50 = 3-15 microM). Additionally, we compared the cytotoxicity of these seven compounds on HeLa cells. Glaucine was the most cytotoxic compound on HeLa cells (IC50 = 8.2 microM) in the series. In order to elucidate their mechanism of action, the binding mode of these molecules to DNA was studied by UV absorption, circular and linear dichroism spectroscopy. The results of the optical measurements indicated that all seven aporphines effectively bind to DNA and behave as typical intercalating agents. Biochemical experiments showed that actinodaphnine, cassythine and dicentrine also interfere with the catalytic activity of topoisomerases in contrast to the four other aporphines. These interactions with DNA may explain, at least in part, the effects observed on cancer cells and on trypanosomes.

Animals↗
PubMed1984

Central monoaminergic effects of two aporphine analogues to the putative serotonin-receptor agonist, 8-hydroxy-2-di-n-propylaminotetralin.

Two aporphine analogues to the potent and selective serotonin (5-HT) agonist, 8-hydroxy-2-di-n-propylaminotetralin (8-OH-DPAT) were studied with regard to their actions upon central monoaminergic systems. The biochemical and behavioural findings indicate that 8-hydroxy-N-methyl-aporphine (8-OH aporphine) and its N-n-propyl analogue (8-OH PNA) possess weak dopamine/noradrenaline antagonist- and agonist-like properties, respectively. In addition, both aporphines seemed to only weakly influence serotoninergic transmission. The latter findings are compared to those of known serotonin agonists (e.g. 8-OH-DPAT), and are discussed with particular reference to the structural requirements for activation of central 5-HT receptors.

Animals↗