title: Preparation and pharmacological activities of 10-homolupinanoyl-2-R-phenothiazines.
abstract: Pursuing our researches on quinolizidinyl derivatives of phenothiazine and on the ground of antidepressive, diuretic, antianginal and antiarrhythmic activities of several 10-(3-dialkylamino) propionylphenothiazines (as chloracizine, moricizine, etc.), six 10-homolupinanoyl-2-R-phenothiazines were prepared and subjected to a broad pharmacological screening with in vivo and in vitro assays. Most of these compounds exerted strong antiarrhythmic activity (compounds 1, 3 and 5 were comparable or superior to lidocaine and quinidine in three tests), calcium antagonism on guinea pig ileum and left atria, antagonism to smooth muscle contractile responses induced by several agents and inhibition of rabbit platelet aggregation induced by PAF and ADP. A few other activities were characteristic of single compounds, as antagonism to central and peripheral effects of oxotremorine 1, moderate antihypertensive activity 5, local anesthetic activity and antagonism to substance P 2, antiinflammatory activity with low or absent gastric irritation 2, 3, powerful saluretic action 6, inhibition of arachidonate induced platelet aggregation 1 and antagonism to PAF induced mortality 1, 4. The last activity is very unusual and deserves further investigation. The capacity of compound 1 to displace specific ligands from several receptors was also investigated. Significant binding for M1 (IC50 = 0.03 microM), M3 (IC50 = 10 microM), sigma receptors and Na+ channels (IC50 = 1 microM) were evidentiated.
authors.affiliation: Istituto Chimico Farmaceutico e Tossicologico, Università di Milano.
authors.forename: A
authors.initials: A
authors.lastname: Sparatore
authors.forename: F
authors.initials: F
authors.lastname: Sparatore
mesh_terms: D000818:Animals; D002491:Central Nervous System Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018492:Dopamine Antagonists; D005260:Female; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D066298:In Vitro Techniques; D007509:Irritants / Q000494:pharmacology; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D051379:Mice; D010276:Parasympatholytics / Q000138:chemical synthesis / Q000494:pharmacology; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D010640:Phenothiazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D017480:Receptors, sigma / Q000187:drug effects / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D013973:Thyrotropin-Releasing Hormone / Q000378:metabolism
chemical_list: D002491:Central Nervous System Agents; D018492:Dopamine Antagonists; D006634:Histamine H1 Antagonists; D007509:Irritants; D016859:Lipoxygenase Inhibitors; D010276:Parasympatholytics; D010640:Phenothiazines; D011976:Receptors, Muscarinic; D011985:Receptors, Serotonin; D017480:Receptors, sigma; D012702:Serotonin Antagonists; D015222:Sodium Channels; D013973:Thyrotropin-Releasing Hormone; D017998:Leukotriene D4