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Synthesis of 1'-methyl-3-phenylspiro[isobenzofuran-1(3H),4'-piperidine] (7a, HP 365) and the demethyl analogue 9a (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 7a 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 9a. Synthesis of analogues was stimulated by discovery of marked inhibition of tetrabenazine-induced ptosis for lead compounds 7a and 9a. Optimal antitetrabenazine activity is associated with the 3-phenylspiro-[isobenzofuran-1(3H),4'-piperidine] moiety where nitrogen is basic. Modification of this moiety by introduction of large nitrogen substituents or a C-3 substituent greater than H significantly reduced antitetrabenazine activity. A series of analogues with aromatic substituents was investigated; however, few of these compounds were significantly more active than 7a and 9a. Compound 9a was selected for additional studies.

The synthesis of 1'-[3-(4-fluorobenzyoyl)propyl]-3-phenylspiro[isobenzofuran-1(3H),4'-piperidine] (2a) and eight halo and methoxy analogues is described. The compounds were generally more potent per os than chlorpromazine in the Sidman avoidance paradigm in rats and less potent than haloperido. 1'-[3-(4-Fluorobenzoyl)propyl]-3-(4-fluorophenyl)spiro[isobenzofuran-1(3H),4'-piperidine] (2e) approached the per os potency of haloperidol in this test and was shown to be active in inhibiting monkey avoidance also. Compound 2e was much less active than haloperidol in antagonizing apomorphine-induced emesis in dogs, apomorphine-induced stereotypy in rats, and amphetamine-induced circling in lesioned rats. This lack of nonselective, dopamine-receptor blocking effects makes 2e attrative as a potential neuroleptic.

Previous studies have shown that the avian progesterone receptor, when in the nontransformed 8 S state, is complexed to another cellular protein having a molecular weight of 90,000. In this report, we show that this receptor-binding protein is indistinguishable from the 90,000-dalton protein which associates in a complex with the Rous sarcoma virus transforming protein, pp60v-src. This identity was established by the following criteria. 1) Monoclonal antibodies directed against the pp60v-src-associated 90-kDa protein recognized the 90-kDa progesterone receptor binding protein in an immunoblot assay. Conversely, monoclonal antibodies that recognize the progesterone receptor binding protein bind to the 90-kDa protein which complexes with pp60v-src. 2) Peptide maps prepared from the 90-kDa proteins immunoprecipitated from chicken cells with monoclonal antibodies directed against either the 90-kDa receptor binding protein or the 90-kDa pp60v-src-associated protein were indistinguishable. 3) Preincubation of the progesterone receptor complex with monoclonal antibodies prepared against the pp60v-src-associated protein caused a shift in the sedimentation of the progesterone receptor. Previous studies have established that the pp60v-src-associated protein is indistinguishable from one of the major heat shock proteins which are induced under a variety of stress conditions in eukaryotic cells. These present studies implicate a new role for this 90-kDa protein in the action of steroid hormones.