ABSTRACT
Molecular modelling studies suggested the synthesis of cis-1,3,4,6,7, 11b-hexahydro-2-methyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline (7a) as a rigid analogue of the atypical antidepressant mianserin. Acylation of 2,2-diphenylethylamine with chloroacetyl chloride gives the chloroacetamide (2). Cyclization of 2 with P2O5 in xylene provides 1-(chloromethyl)-3,4-dihydro-4-phenylisoquinoline (3). Amination of 3, followed by reduction, gives the isomeric (aminomethyl)tetrahydroisoquinolines (4a and 5). Treatment of 4a with diethyl oxalate, followed by reduction of the diamide with borane, provides 7a. A variety of N-substituted, aromatic substituted, and optically resolved derivatives were prepared and evaluated for anticholinergic, antihistaminic, and antidepressant activity. In particular, the target cis isomer 7a as predicted from the modelling studies appears to possess excellent atypical antidepressant activity. This activity resides in the (+)-S,S optical isomer 10, which has the same absolute configuration as (+)-mianserin.
Subject(s)
Antidepressive Agents/chemical synthesis , Isoquinolines/chemical synthesis , Animals , Brain/metabolism , Dogs , Imipramine/pharmacology , Isoquinolines/pharmacology , Mianserin/analogs & derivatives , Mianserin/pharmacology , Models, Molecular , Pyrilamine/metabolism , Quinuclidinyl Benzilate/metabolism , Rats , Receptors, Cholinergic/metabolism , Receptors, Histamine/metabolismABSTRACT
Hypoxia or electroconvulsive shock (ECS) was administered to two strains of rats following one trial passive avoidance training. ECS produced retrograde amnesia in the Blue Spruce Farms Long Evans hooded rat when administered within 10 sec after training and in the Charles River albino rat when administered within 75 sec after training. Hypoxia was effective in producing retrograde amnesia when administered up to 40 min after training in the hooded rat but only when administered between 20 and 30 min after training in the albino rat. The importance of strain variability is discussed.
