Quinolizidine derivatives as potential antitumoral agents

The activity against lymphocytic leukemia P 388 has been evaluated for thirteen compounds bearing a quinolizidine moiety bound respectively to a phenothiazine nucleus or other isosteric tricyclic systems (12-17), as well to a quinoxalinone (18-20) or an indole (21-24) nucleus. All tested compounds resulted inactive

Synthesis and antileukemic activity of 1-[(quinolizidinylalkyl)amino]4/7-R-thioxanthen-9-ones

Fifteen 1-(quinolizidinylalkyl)amino derivatives of thioxanthenone bearing different substituents on position 4 and 7 were prepared and tested in mice against lymphocytic leukemia P 388. These compounds were inactive or displayed only borderline activity (compounds 1, 10, 15)

Cytisine derivatives as ligands for neuronal nicotine receptors and with various pharmacological activities

Neuronal nicotinic acetylcholine receptors (nAChRs) form a family of ACh-gated cation channels made up of different subtypes. They are widely distributed in peripheral and central nervous systems and are involved in complex cerebral processes as learning, memory, nociception, movement, etc. The possibility that subtype-selective ligands be used in the treatment of CNS disorders promoted the synthesis of a large number of structural analogues of nicotine and epibatidine, two very potent nAChR agonists. Pursuing our long standing research on the structural modification of quinolizidine alkaloids, we devoted our attention to cytisine, another very potent ligand for many nAChR subtypes. Thus a systematic structural modification of cytisine was undertaken in order to obtain compounds of potential therapeutic interest at peripheral as well as central level, with a particular concern for achieving nAChR subtype selective ligands. Up to the present more than 80 cytisine derivatives, mainly of N-substitution and a few by modifying the pyridone ring, have been prepared. The biological results, which concern so far about an half of the prepared compounds, indicate that the introduction of a nitro group in position 3 of the pyridone nucleus further enhances the high affinity of cytisine, while the introduction of substituents on the basic nitrogen, though reducing in different degrees the affinity, gives rise to compounds with a higher selectivity for central (\u3b14\u3b22) versus gangliar (\u3b13-containing) receptor subtype. On the other hand, the analgesic, antihypertensive and inotropic activities found in some N-substituted cytisines, represent an attractive starting point for the development of more active compounds

Detection and mass spectrometric characterization of the major urinary and fecal metabolites of 9-methyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]-quinolizine in the rat

The metabolic fate of 9-methyl 1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine (MIQ), a compound with promising pharmacological action on the CNS system, was investigated in the rat after an oral dose of 200 mg/kg, the maximal tolerated dose. Urine and feces were collected, exhaustively extracted with organic solvents and the metabolites detected by TLC analysis. The structures of the isolated metabolites were characterized by several mass spectrometry techniques (FD, EI, CI) and, in some cases, confirmed by synthesis. The major metabolic pathways of MIQ in the rat involve: C-oxidation of the methyl group in position 9 to a primary alcohol and to a carboxylic acid, N-oxidation of basic nitrogen and C-oxidation of the quinolizidine nucleus, probably at position 7

[3,6-disubstituted 1-lupinylquinoxalin-2(1H)-ones of pharmacological interest. Effect on acquisition and modification of a conditioned avoidance response in rats]

Fifteen N-lupinyl derivatives of 3-methyl-, 3-phenyl- and 3-benzylquinoxalin-2(1H)-one, variously substituted on position 6 (R = CH3O, CH3, Cl, CF3), were prepared. Of these, all 1-lupinyl-3-methylquinoxalin-2-ones exhibit a high degree of deconditioning activity in the tests of acquisition and modification of a conditioned avoidance response (C.A.R.) in rats. In both tests, compounds (II) and (IV), with R = CH3O and Cl respectively, proved more active than chloropromazine