title: Preparation and pharmacological activities of homolupinanoyl anilides.
abstract: On the pattern of well known dialkylaminoacyl anilides, a set of N-homolupinanoyl anilides was prepared and subjected to a broad pharmacological screening with in vivo and in vitro assays. As expected most compounds exhibited a strong antiarrhythmic activity, often comparable or superior to that of lidocaine and quinidine. Compound 1 exhibited an unusual profile as antiarrhythmic, being devoid of local anesthetic activity, calcium channel and beta adrenoceptor antagonism. Calcium channel blocking activity was seen in all aminobenzophenone derivatives, but not in the simpler anilides. Noteworthy are also the capacity of compound 7 to protect mice from a lethal dose of KCN, the moderate antihypertensive activity of 10 and, above all, the antagonism to guinea pig ileum contractile responses induced by several agents exhibited by compound 11, which deserves further investigation for a potential use in irritable bowel syndrome. Compound 11 showed also good relaxant activity on tracheal strips and inhibitory activity against arachidonate induced platelet aggregation. Finally, compound 11 displaced several radioligands from their respective binding sites. Most potent was displacement of [3H]pirenzepine (IC50 < or = 0.01 microM) from M1 binding sites of rat brain, while displacement of [3H] methylscopolamine from rat heart (M2) and submaxillary salivary glands (M3) preparations was much weaker (IC50 approximately equal to 2.4 and 1.3 microM, respectively).
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: D058668:Adrenergic alpha-1 Receptor Antagonists; D058671:Adrenergic beta-1 Receptor Antagonists; D000813:Anilides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001577:Benzophenones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001760:Bleeding Time; D003486:Cyanides; D019004:Galanin; D006168:Guinea Pigs; D000860:Hypoxia / Q000139:chemically induced / Q000188:drug therapy; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D009479:Neuropeptides / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D010972:Platelet Activating Factor / Q000378:metabolism; D011485:Protein Binding; D011680:Pupil / Q000187:drug effects; D011807:Quinolizines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D018100:Receptors, Histamine H3 / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D058671:Adrenergic beta-1 Receptor Antagonists; D000813:Anilides; D000889:Anti-Arrhythmia Agents; D001577:Benzophenones; D003486:Cyanides; D019004:Galanin; D009479:Neuropeptides; D010455:Peptides; D010972:Platelet Activating Factor; D011807:Quinolizines; D018100:Receptors, Histamine H3; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D018047:Receptors, Purinergic P1