Synthesis of 1''-methyl-3-phenylspiro[isobenzofuran-1(3H),4''-piperidine] (HP 365) and the demethyl analog (HP 505) was prompted by recognition of an aminoalkyl(aryl)isobenzofuran moiety common to the antidepressants talopram (Lu 3-010) and trans-10,11-dihydro-5,10-epoxy-5-[3-(methylamino)propyl]-5H-dibenzo[a,d]cyclohepten-11-ol (MK-940). Convenient laboratory synthesis of HP 365 was provided by lithiation of 2-bromobenzhydryl methyl ether, followed by addition of 1-methyl-4-piperidone and acid-catalyzed cyclization. N-Dealkylation by standard methods afforded HP 505. Synthesis of analog was stimulated by discovery of marked inhibition of tetrabenazine-induced ptosis for lead compounds HP 365 and HP 505. Optimal antitetrabenazine activity is associated with the 3-phenylspiro[isobenzofuran-1(3H),4''-piperidine] moiety where N is basic. Modification of this moiety by introduction of large N substituents or a C-3 substituent > H significantly reduced antitetrabenazine activity. A series of analogs with aromatic substituents was investigated; few of these compounds were significantly more active than HP 365 and HP 505. Compound HP 505 was selected for additional studies.