PREPARATION AND PHARMACOLOGICAL ACTIVITIES OF 10-HOMOLUPINANOYL-2-R-PHENOTHIAZINES

Pursuing our researches on quinolizidinyl derivatives of phenothiazine and on the ground of antidepressive, diuretic, antianginal and antiar rhythmic activities of several 10-(3-dialkylamino) propionylphenothiaz ines (as chloracizine, moricizine, etc.), six 10-homolupinanoyl-2-R-ph enothiazines were prepared and subjected to a broad pharmacological sc reening with in vivo and in vitro assays. Most of these compounds exer ted strong antiarrhythmic activity (compounds 1, 3 and 5 were comparab le or superior to lidocaine and quinidine in three tests), calcium ant agonism on guinea pig ileum and left atria, antagonism to smooth muscl e contractile responses induced by several agents and inhibition of ra bbit platelet aggregation induced by PAF and ADP. A few other activiti es were characteristic of single compounds, as antagonism to central a nd peripheral effects of oxotremorine 1, moderate antihypertensive act ivity 5, local anesthetic activity and antagonism to substance P2, ant iinflammatory activity with low or absent gastric irritation 2,3, powe rful saluretic action 6, inhibition of arachidonate induced platelet a ggregation 1 and antagonism to PAF induced mortality 1, 4. The last ac tivity is very unusual and deserves further investigation. The capacit y of compound 1 to displace specific ligands from several receptors wa s also investigated. Significant binding for M(1) (IC50=0.03 mu M), M( 3) (IC50=10 mu M), sigma receptors and Na+ channels (IC50=1 mu M) were evidentiated.