benzofurans and Dyskinesia--Drug-Induced

The synthesis of a series of 4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)methyl-2-arylbenzofuran and 4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)methylbenzofuran-2-carboxamide derivatives as novel alpha(2C)-adrenergic receptor antagonists are described. Their affinity at three different human alpha(2)-adrenergic receptors is reported, and some of these compounds exhibited high affinity for the alpha(2C)-adrenergic receptor with high subtype selectivity. Among them, compound 10e has been found to show the anti-L-dopa-induced dyskinetic activity in marmosets. The structure-activity relationship of these compounds is also discussed.

Topics: Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Benzofurans; Callithrix; Dopamine Agents; Dyskinesia, Drug-Induced; Humans; Indicators and Reagents; Isoquinolines; Levodopa; Receptors, Adrenergic, alpha-2; Structure-Activity Relationship

To determine: (1) whether the apparent lack of efficacy of dopamine D1 (D1) antagonists in the clinic might be attributable to development of tolerance to antipsychotic effects; and (2) whether combined D1 and D2 antagonism might contribute to clozapine's clinical profile, eight Cebus apella monkeys were chronically treated with a D1 antagonist (NNC 756) ((+)-8-chloro-7-hydroxy-3-methyl-5-(7-(2,3- dihydrobenzofuranyl)-2,3,4,5-tetrahydro-1H-3-benzazepine), a D2 antagonist (raclopride) or a combination of the two antagonists. Prior neuroleptic exposure had resulted in oral dyskinesia in seven monkeys and sensitization to dystonia in all, yielding a model for acute and chronic extrapyramidal side effects (EPS). Dextroamphetamine-induced motoric unrest and stereotypies were used as a psychosis model. We found tolerance toward dystonic symptoms during D1 and D1 + D2 treatments but not during D2 treatment. D2 but not D1 or D1 + D2 antagonism caused exacerbation of dyskinesia. Both D1 and D1 + D2 antagonism were superior to D2 antagonism alone in counteracting the amphetamine-induced behaviors, with no tolerance to antiamphetamine effects. These findings suggest: (1) reasons other than tolerance (e.g., differences among antagonists) may explain the lack of efficacy in clinical trials with D1 antagonists; and (2) that D1 antagonism alone or combined and modest D1 and D2 antagonism offers the potential of antipsychotic efficacy with a lower risk of EPS than traditional D2 antagonism. Further clinical trials with D1 or combined D1 and D2 antagonists are, therefore, recommended.

Topics: Amphetamine; Animals; Arousal; Basal Ganglia Diseases; Benzazepines; Benzofurans; Cebus; Dopamine Agents; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Interactions; Dyskinesia, Drug-Induced; Dystonia; Male; Motor Activity; Raclopride; Receptors, Dopamine D1; Receptors, Dopamine D2; Salicylamides; Stereotyped Behavior

Previous studies in non-human primates have shown that tolerance to dystonia occurs during chronic dopamine D1 (D1) but not D2 antagonism and induction/aggravation of oral dyskinesia (TD) during D2 but not D1 antagonism. We were therefore interested in determining the effects of combined chronic D1 + D2 antagonism on dystonia and dyskinesia. To this intent, 8 male Cebus apella monkeys were treated 10 weeks with gradually increasing doses of D1 antagonist (NNC 112) + a D2 antagonist (raclopride), followed by 2 weeks of treatment with the D2 antagonist alone. Due to previous neuroleptic exposure, 5 monkeys had TD and all were sensitized to dystonia. During the combined antagonist treatment, tolerance to dystonia occurred; the tolerance disappearing upon discontinuation of the D1 antagonist and continuation of the D2 antagonist alone. Parallel to these results, improvement of TD was seen during the combined antagonist treatment with worsening during the D2 antagonist alone. Both the combined antagonists and the D2 antagonist alone resulted in moderate/severe bradykinesia, with no tolerance. These findings indicate that supplementation of traditional D2 antagonism with a D1 antagonist would lessen the risk of dystonia and allow alleviation of preexisting TD, though parkinsonian side effects might still occur. The findings further indicate that separate dopaminergic mechanisms control dystonia/dyskinesia and parkinsonism.

Topics: Animals; Basal Ganglia Diseases; Benzazepines; Benzofurans; Cebus; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Male; Raclopride; Receptors, Dopamine D1; Time Factors

Eight Cebus apella monkeys previously exposed to D1 and D2 antagonists were treated subcutaneously for 8 weeks with the D1 antagonist NNC 756 (0.01 mg/kg), followed by a wash-out period of 4 weeks and treatment with the D2 antagonist raclopride for 8 weeks (end doses 0.01 mg/kg). NNC 756 induced no dystonia, while marked dystonia was induced by raclopride. Mild tolerance to the dystonia-inducing effect of raclopride slowly developed. Both drugs induced significant sedation and mild bradykinesia. Sedation induced by NNC 756 was stronger than that of raclopride, while no differences were found regarding bradykinesia. The sedative effect of both NNC 756 and raclopride increased over time during chronic treatment. No changes in bradykinesia developed. No significant dyskinesia was induced by NNC 756, while raclopride significantly induced both acute and tardive oral dyskinesia. Furthermore, raclopride-induced acute dyskinesia worsened during chronic treatment. Concomitant treatment with NNC 756 tended to reduce the D1 agonist SKF 81297-induced dyskinesia and grooming, while concomitant treatment with raclopride increased SKF 81297-induced dyskinesia and tended to decrease SKF 81297-induced grooming. Chronic treatment with raclopride induced supersensitivity to both the D2/D3 agonist LY 171555 and SKF 81297, while chronic NNC 756 treatment only induced supersensitivity to SKF 81297. The findings indicate that D1 antagonists may induce less dystonia and oral dyskinesia as compared with D2 antagonists and support the hypothesis of both a permissive and an inhibitory interaction between D1 and D2 receptor systems.

Topics: Animals; Basal Ganglia Diseases; Behavior, Animal; Benzazepines; Benzofurans; Cebus; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dyskinesia, Drug-Induced; Ergolines; Grooming; Hypnotics and Sedatives; Male; Motor Activity; Quinpirole; Raclopride; Receptors, Dopamine D1; Receptors, Dopamine D2; Salicylamides

In order to relate the effects of pharmacological intervention to neuroleptic induced increases in oral activity rats were treated continuously (7 mg/kg per week) or discontinuously (7 mg/kg per week or 2 mg/kg per week) with haloperidol for 6 months. Only the two intermittently treated groups developed persisting increases in vacuous chewing movements (VCM) following drug withdrawal. Opposed to control animals and continuously treated rats, the discontinuously treated groups demonstrated significant elevation in mouth movements following stimulation with the dopamine (DA) D1 receptor agonist SK&F 38393 (23 mg/kg), whereas they did not response to an acute challenge with the selective DA D1 receptor antagonist NNC-756 (0.1 mg/kg). The DA D2 receptor antagonist raclopride (1 mg/kg) provoked a general fall in VCM; however, this was only significant in rats treated intermittently with haloperidol 7 mg/kg per week and in control rats. Intermittent neuroleptic treatment also increased apomorphine-induced stereotypy. The effect of challenge with the anticholinergic drug scopolamine (0.25 mg/kg) was not related to oral activity; furthermore, the finding of severe agitation in rats tested with the latter drug points to caution in the interpretation of rating of rats treated with anticholinergics. These results support that intermittent ingestion of neuroleptic drugs lead to long-lasting increases in VCM. They also suggest a relation of persisting elevated oral activity to supersensitivity to DA receptor agonists, as opposed to subsensitivity to D1 receptor antagonists.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Antipsychotic Agents; Apomorphine; Benzazepines; Benzofurans; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dyskinesia, Drug-Induced; Haloperidol; Male; Parasympathetic Nervous System; Raclopride; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Salicylamides; Scopolamine; Stereotyped Behavior

Rats were treated intermittently or continuously with the dopamine D1 receptor antagonist NNC-756 for 15 weeks. Two weeks after withdrawal they were challenged with the dopamine D1 receptor agonist SK&F 38393, either alone or after pretreatment with NNC-756. Neither treatment regimen resulted in irreversible increases in oral activities when treated rats were compared with controls; however, transient elevations were observed in the beginning of treatment in the continuously treated group and in the withdrawal phase in the discontinuously treated group. Furthermore, discontinuous treatment resulted in within-group elevations in vacuous chewing movements and tongue protrusions after withdrawal. Dopamine D1 receptor supersensitivity was not observed after challenge with the dopamine D1 receptor agonist. NNC-756 efficiently blocked the behavioural response to stimulation with SK&F 38393. Both treatment regimens resulted in the development of rigidity and catalepsy. The present study suggests that treatment with selective dopamine D1 receptor antagonists is less likely to cause irreversible oral dyskinesia than is treatment with classical neuroleptic drugs.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Benzazepines; Benzofurans; Dopamine Antagonists; Drug Administration Schedule; Dyskinesia, Drug-Induced; Face; Jaw; Male; Rats; Rats, Wistar; Tongue; Tremor