Bifunctional Variations of the Antidepressant Amitriptyline Theme

In an attempt to inhibit uptake sites for biogenic amines, the following “rigid” and “flexible” bifunctional analogues of amitriptyline of various topologies have been synthesized and evaluated as antidepressants: 5,7-bis(3-dimethylaminopropylidene)-12,13,15,16-tetrahydrobisbenzocyclohepta [7,6-a;6′,7′-d]bezene (7), 5,13-bis(3-dimethylaminopropylidene)-7,8,15,16-tetrahy-drobisbenzocyclohepta[6,7-a;6′,7′-d]benzene (8), 9,18-bis(3-dimethylaminopropylidene)-4b,4c, 13b, 13c-tetrahydrotetrabenzo[a,d,h,k]dicycloheptacyclobutene (9), and 1,2-bis[3,3′-(5-N,N-dimethylaminopropylidene[5H]dibenzo[a,d]cyclohepten)]ethane (12). All were active as measured by the uptake inhibition of ³H-serotonin into human blood platelets. Their structure-activity relationships revealed somewhat lower activity as compared with amitriptyline (1) but indicated the bifunctional amitriptylines can still interact with the uptake site. The synthesis and molecular structures including stereochemistry of the chiral pentacyclic aminoalcohol precursors (R,R and S,S)-4 and (R,S)-5 are reported. Strong intramolecular O-H…N bonding in 4 and 5 are noted.