Synthesis and pharmacological study of the thiophene analogue of taclamine, QM-7184, a new neuroleptic drug with potent alpha-adrenoceptor blocking activity.
The method of synthesis and the pharmacological evaluation of (+/-)-6-trans-8b,9,10,11,12,13-trans-13a-Octahydro-5H-7-thia-12a-azabenzo[f]naphth[1,2,3-c,d] azulene (QM-7184), a thiophene analogue of taclamine, are reported. This new drug shows, at variance with the prototype, a neuroleptic profile in rodents. QM-7184 decreases the spontaneous motor activity, blocks the stereotyped behaviour induced by dopaminergic stimulants and reduces conditioned avoidance responses. In all of these tests, the new drug is less potent than the typical neuroleptics haloperidol or butaclamol. Taclamine does not show, as expected, any neuroleptic activity. Like other neuroleptics, QM-7184 blocks striatal dopaminergic receptors and consequently increases the concentration of homovanillic acid and displaces [3H]spiperone binding, although it is a less potent displacer than haloperidol or butaclamol. QM-7184 shows, however, a high affinity for alpha-noradrenergic receptors, both in the cortex and in the striatum, which is about 20 and 90 times higher than those of haloperidol and butaclamol, respectively. In view of the recently suggested role for norepinephrine in the etiology of schizophrenia, it is speculated that drugs of this type may be of interest in the treatment of psychotic illness.
D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis*; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000378:metabolism; D001581:Benzothiadiazines; D001921:Brain / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced; D055598:Chemical Phenomena; D002621:Chemistry; D003342:Corpus Striatum / Q000378:metabolism; D003508:Cycloheptanes / Q000138:chemical synthesis* / Q000494:pharmacology; D003913:Dextroamphetamine / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects; D006168:Guinea Pigs; D006719:Homovanillic Acid / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010095:Oxotremorine / Q000037:antagonists & inhibitors; D051381:Rats; D013239:Stereotyped Behavior / Q000187:drug effects; D013876:Thiophenes
D000317:Adrenergic alpha-Antagonists; D000927:Anticonvulsants; D014150:Antipsychotic Agents; D001581:Benzothiadiazines; D003508:Cycloheptanes; D013876:Thiophenes; D010095:Oxotremorine; C039927:QM 7184; D003913:Dextroamphetamine; D006719:Homovanillic Acid