ABSTRACT
A series of pharmacologically interesting 1- and 2-[omega-(4-arylpiperazin-1-yl)alkyl]-1,2,3-benzotriazoles, compounds 1-27, were synthesized (Scheme) and subjected to various biological studies to identify structure-activity relationships (SAR). The new compounds were found to exhibit good non-selective binding affinity towards the alpha1-adrenoreceptor (Table 1). In several cases, high functional antagonism was observed towards the alpha1A-, alpha1B-, and alpha1D-adrenoreceptor subtypes (Table 2). The selectivity for these three subtypes was comparable with or superior to that displayed by the standard drug prazosin. The most-common selectivity rank order was alpha1D > alpha1B > alpha1A, followed by alpha1B > alpha1D > alpha1A. In functional experiments, antagonism towards the alpha2-adrenoreceptor was generally low; however, a few compounds were endowed with significant antagonist properties (pA2 values of up to 7.87).
Subject(s)
Adrenergic alpha-Agonists/chemistry , Adrenergic alpha-Antagonists/chemistry , Triazoles/chemistry , Triazoles/pharmacology , Adrenergic alpha-Agonists/pharmacology , Adrenergic alpha-Antagonists/pharmacology , Animals , Aorta/drug effects , Male , Molecular Structure , Muscle Contraction/drug effects , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Vas Deferens/drug effectsABSTRACT
A set of ten 2-phenyl-3-(quinolizidin-1-yl)-5-substituted indoles was prepared through the Fischer cyclization of lupinyl- and epi-lupinylphenylketone 4-substituted phenylhydrazones. Compounds were tested for antiaggregating activity on human platelets activated by adenosine diphosphate (ADP), collagen and adrenaline. At 2.5 x 10(-4) M concentration most compounds strongly inhibited the aggregation induced by all the agonists considered and many of them still displayed good activity at 0.625 x 10(-4) M concentration. The least active (1c) and one of the most active (1d) compounds were also tested for antiaggregating activity on rabbit platelets activated by ADP, PAF and sodium arachidonate. Both the compounds were active against ADP and PAF, but only 1d inhibited the arachidonate-induced aggregation (100% at 8 x 10(-6) M concentration) and increased the bleeding time in mice. The same compounds were subjected to a general pharmacological screening and found to display several activities; of particular interest was the dose dependent reduction of serum cholesterol and heparin precipitating betalipoproteins in hypercholesterolemic mice exerted by 1c, which was still significant at the oral dose of 10 mg/kg.
Subject(s)
Indoles/chemical synthesis , Indoles/pharmacology , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Quinolizines/chemical synthesis , Quinolizines/pharmacology , Adenosine Diphosphate/antagonists & inhibitors , Adenosine Diphosphate/pharmacology , Analgesics/pharmacology , Animals , Anti-Arrhythmia Agents/pharmacology , Collagen/antagonists & inhibitors , Collagen/pharmacology , Cyclization , Diuretics/pharmacology , Drug Evaluation, Preclinical , Epinephrine/antagonists & inhibitors , Epinephrine/pharmacology , Humans , Hypolipidemic Agents/pharmacology , In Vitro Techniques , Indicators and Reagents , Indoles/toxicity , Lethal Dose 50 , Mice , Pain Measurement/drug effects , Platelet Aggregation Inhibitors/toxicity , Quinolizines/toxicity , Rabbits , Spectrophotometry, Infrared , Spectrophotometry, UltravioletABSTRACT
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 (alpha(4)beta(2)) versus gangliar (alpha(3)-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.
