ABSTRACT
A series of aminoisopropanoloxy derivatives of xanthone has been synthesized and their pharmacological properties regarding the cardiovascular system has been evaluated. Radioligand binding and functional studies in isolated organs revealed that title compounds present high affinity and antagonistic potency for α1-(compound 2 and 8), ß-(compounds 1, 3, 4, 7), α1/ß-(compounds 5 and 6) adrenoceptors. Furthermore, compound 7, the structural analogue of verapamil, possesses calcium entry blocking activity. The title compounds showed hypotensive and antiarrhythmic properties due to their adrenoceptor blocking effect. Moreover, they did not affect QRS and QT intervals, and they did not have proarrhythmic potential at tested doses. In addition they exerted anti-aggregation effect. The results of this study suggest that new compounds with multidirectional activity in cardiovascular system might be found in the group of xanthone derivatives.
Subject(s)
Adrenergic Antagonists/chemical synthesis , Drug Design , Xanthones/chemistry , Adrenergic Antagonists/metabolism , Adrenergic Antagonists/pharmacology , Animals , Blood Pressure/drug effects , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/metabolism , Calcium Channel Blockers/pharmacology , Calcium Channels/chemistry , Calcium Channels/metabolism , Heart Rate/drug effects , Inhibitory Concentration 50 , Male , Platelet Aggregation/drug effects , Radioligand Assay , Rats , Rats, Wistar , Receptors, Adrenergic, alpha/chemistry , Receptors, Adrenergic, alpha/metabolism , Receptors, Adrenergic, beta/chemistry , Receptors, Adrenergic, beta/metabolism , Structure-Activity Relationship , Verapamil/chemistry , Xanthones/metabolism , Xanthones/pharmacologyABSTRACT
A series of new xanthone derivatives with piperazine moiety [1-7] was synthesized and evaluated for their pharmacological properties. They were subject to binding assays for α1 and ß1 adrenergic as well as 5-HT1A, 5-HT6 and 5-HT7b serotoninergic receptors. Five of the tested compounds were also evaluated for their anticonvulsant properties. The compound 3a 3-methoxy-5-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-9H-xanthen-9-one hydrochloride exhibited significantly higher affinity for serotoninergic 5-HT1A receptors (Ki=24 nM) than other substances. In terms of anticonvulsant activity, 6-methoxy-2-{[4-(benzyl)piperazin-1-yl]methyl}-9H-xanthen-9-one (5) proved best properties. Its ED50 determined in maximal electroshock (MES) seizure assay was 105 mg/kg b.w. (rats, p.o.). Combining of xanthone with piperazine moiety resulted in obtaining of compounds with increased bioavailability after oral administration.
Subject(s)
Anticonvulsants/chemical synthesis , Piperazines/chemistry , Xanthones/chemistry , Administration, Oral , Animals , Anticonvulsants/pharmacokinetics , Anticonvulsants/therapeutic use , Drug Evaluation, Preclinical , Electroshock , Half-Life , Kinetics , Piperazine , Protein Binding , Rats , Receptor, Serotonin, 5-HT1A/chemistry , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Serotonin/chemistry , Receptors, Serotonin/metabolism , Seizures/drug therapy , Xanthones/pharmacokinetics , Xanthones/therapeutic useABSTRACT
Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na(+) channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 - for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca(2+)s channels are not any more divided to T, L, N, P/Q, and R, but they are described as Ca(v)1.1-Ca(v)3.3, with even newer nomenclature α1A-α1I and α1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs.
Subject(s)
Calcium Channel Blockers/chemistry , Ion Channels/antagonists & inhibitors , Potassium Channel Blockers/chemistry , Sodium Channel Blockers/chemistry , Animals , Calcium Channel Blockers/pharmacology , Calcium Channel Blockers/therapeutic use , Calcium Channels/chemistry , Calcium Channels/metabolism , Central Nervous System Diseases/drug therapy , Humans , Ion Channels/metabolism , Ligand-Gated Ion Channels/antagonists & inhibitors , Ligand-Gated Ion Channels/metabolism , Potassium Channel Blockers/pharmacology , Potassium Channel Blockers/therapeutic use , Potassium Channels/chemistry , Potassium Channels/metabolism , Sodium Channel Blockers/pharmacology , Sodium Channel Blockers/therapeutic use , Sodium Channels/chemistry , Sodium Channels/metabolism , Transient Receptor Potential Channels/antagonists & inhibitors , Transient Receptor Potential Channels/metabolismABSTRACT
A series of aroxyethylamines (1-10) have been previously evaluated for antihypertensive and adrenolytic properties. Of the derivatives tested, four (compounds 4, 7, 8 and 10) displayed significant antihypertensive activity and binding affinities for alpha- and beta-adrenergic receptors. As a continuation of our study, we present here the in vivo and in vitro antiarrhythmic activity of compounds 1-10, as well as their electrocardiographic properties. Only compounds 4, 7, 8 and 10 demonstrated strong antiarrhythmic activity in adrenaline induced arrhythmia after intravenous and oral administration. In addition, compounds 4 and 7 significantly decreased heart rhythm disturbances in arrhythmia induced by coronary artery occlusion and reperfusion. The pharmacological results and receptor binding studies suggest that the antiarrhythmic activity of the compounds tested may be related to their adrenolytic properties. Moreover, the presence of a methoxyphenylpiperazine moiety seems to be required for their pharmacological activity.
