Cytisine derivatives as high affinity nAChR ligands: synthesis and comparative molecular field analysis.

A number of new N-substituted cytisine derivatives were prepared and tested, along with similar compounds already described by us and others, as high affinity neuronal acetylcholine receptor ligands. Structure-affinity relationships were discussed in the light of our recently proposed pharmacophore model for nicotinic receptor agonists. The most significant physicochemical interactions modulating the receptor-ligand binding were detected at the three dimensional (3D) level by means of comparative molecular field analysis (CoMFA). The best predictive PLS model was a single-field steric model showing good statistical figures: n = 17, Q2 = 0.717, s(ev) = 0.566, r2 = 0.942, s = 0.275.

Synthesis and preliminary pharmacological evaluation of some cytisine derivatives.

Thirty-one N-derivatives of cytisine were prepared in order to modify its pharmacological profile and to obtain compounds of potential therapeutic interest either at a peripheral or central level, particularly as nicotinic ligands with improved ability to cross the blood-brain barrier. Actually, with the introduction of different kinds of substituent on the basic nitrogen of cytisine a variety of activities were observed, both in vivo (analgesic, dopamine antagonism, antihypertensive, inhibition of stress-induced ulcers, antiinflammatory, protection from PAF-induced mortality, hypoglycemic) and in vitro (positive cardio-inotropic, beta-adrenergic antagonism, alpha 1- and alpha 2-antagonism, inhibition of PAF-induced platelet aggregation). Six randomly selected compounds were tested for the ability to recognize a central nicotinic receptor and four of them exhibited Ki values in the range 30-163 nM.

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.

Synthesis and antimicrobial activity of arylazoenamines.

The possibility to obtain new arylazoenamines endowed with antifungal activity was examined by reacting with acids the arylhydrazones of several keto- and aldo-tert, amines as dimethyl-3-aminoacetone, 3-quinuclidinone, 1-methyl-3-piperidone and 2-formyl-1-methylpyrrolidine. The reaction was successful only in the last two cases. From each 1-methyl-3-piperidone arylhydrazone two isomeric arylazoenamines were formed, which were identical with those obtained from the analogous arylhydrazone of 2-formyl-1-methylpyrrolidine. The structure of these compounds was settled on the ground of UV, IR, NMR and mass spectra and confirmed by means of X-ray analysis. A mechanism is proposed for the formation of arylazoenamines through the contraction of piperidine ring and enlargement of the pyrrolidinic one. The prepared compounds [3-arylazo-1-methyl-delta 2-piperideines 17 and 1-methyl-2(arylazo)methylene pyrrolidines 18 exhibited only a very weak antibacterial activity, but were moderately active against several Candida species and other yeast-like fungi.