Novel tetracyclic spiropiperidines. 1. 3-Aryl-1,3-dihydrospiro[benzo[c]thiophene-1,4'-piperidines] as potential antidepressants

Abstract

A series of 3-aryl-1,3-dihydrospiro[benzo[c]thiophene-1,4'-piperidine] derivatives was synthesized and evaluated pharmacologically for potential psychotropic activity. Potent antidepressant-like activity was noted throughout the series, as assessed by tetrabenazine (TBZ) ptosis prevention in mice and potentiation of 5-hydroxytryptophan (5-HTP) induced behavioral effects in rats. A possible therapeutic advantage of the title compounds appears to be the overall low anticholinergic potential in comparison with the classic tricyclic antidepressants. Several congeners with nuclear halogen substitution also exhibited CNS stimulant properties, as evidenced by their ability to induce a dopamine agonist-like stereotypy and to increase the spontaneous motor activity in mice.

Synthesis and Structure−Activity Relationships of N-Propyl-N-(4-pyridinyl)-1H-indol-1-amine (Besipirdine) and Related Analogs as Potential Therapeutic Agents for Alzheimer's Disease

“…Biological Methods. Procedural details for the in vivo prevention of tetrabenazine-induced (TBZ) ptosis 41,42 and reversal of scopolamine dementia dark avoidance (SDDA), 6,43 and in vitro inhibition of synaptosomal biogenic amine (norepinephrine, serotonin, dopamine) uptake 6,44 and inhibition of [ 3 H]quinuclidinyl benzilate (QNB), 24,26,44 [ 3 H]-N-methylscopolamine, 35 [ 3 H]SCH23390, 44 [ 3 H]spiroperidol, 44 [ 3 H]WB4101, 44,45 [ 3 H]clonidine, 46 [ 3 H]yohimbine, 47 [ 3 H]idazoxan, 31,48 [ 3 H]-8-hydroxy-2-(di-n-propylamino)tetralin (DPAT), 51 [ 3 H]dihydromorphine (DHM), 52 [ 3 H]bremazocine, 53 [ 3 H]pirenzepine, 54 [ 3 H]oxotremorine-M 55 and [ 3 H]-N-methylcarbamylcholine 56 binding were previously reported. In vitro inhibition of acetylcholinesterase was determined by the method of Ellman.…”

TiCl4-Mediated Preparation of Thiophthalide Derivatives via Formal Thio-Passerini Reactions

“…Yet, talsupram (Lu 5-003), one of the most studied members of this family, has been identified as a very potent norepinephrine reuptake inhibitor, while other 1,3-dihydro-benzo­[ c ]­thiophenes have similarly showed interesting psychotropic activities (Figure ). − Thiophthalides, on the other hand, are equally stimulating targets considering that some of them display antithrombotic, anticonvulsant, and analgesic properties. , …”

“…Whereas these compounds are typically synthesized through multistep processes or by nucleophilic additions onto thiophthalic anhydride, ,,, the restricted available methods for their preparation have most likely hampered their use in medicinal chemistry. Accordingly, in order to allow a more thorough evaluation of the pharmacological potential of this so far overlooked chemical space, the development of new synthetic methods is highly desirable.…”