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The investigation of dispiro and fused ring tricyclic analogues of ethylenediamine type antihistaminics Stephanson, Lawrence Gerald

Abstract

The synthesis and pharmacological testing of two series of compounds for use in the investigation of the steric and electronic nature of the antihistaminic receptor is described. The dimethylaminoacetyl derivatives of 7-amino-14-azadispiro[5.1.5.2] -pentadecan-15-one and 8-amino-16-azadispiro[6.1.6.2] heptadecan-17-one and the methiodide salts of these compounds were synthesized. The di-methylaminoacetyl derivatives of the reduced ring systems, 7-amino-14-azadispiro[5 .1.5 .2] pentadecane and 8-amino-16-azadispiro [6 .1.6 .2] heptadecane, and the dimethiodide salts were also synthesized. Suitable compounds in this series were tested for local anesthetic activity by the guinea pig intradermal wheal method and for antihistaminic and antimus-carinic activity in isolated guinea pig ileum. Several of the compounds in this series were also screened for general activity and acute toxicity. The compounds in this series were inactive or showed only a very low order of activity. The 2-dimethylaminoethyl derivatives of carbazole, 1,2,3,4-tetra-hydrocarbazole, dodecahydrocarbazole, 1,2,3,4-tetrahydrocyclopent[b] -indole, dodecahydrocyclopent [b] indole, 5,6,7,8,9,10-hexahydrocyclohept-[b] indole, tetradecahydrocyclohept[b] indole, diphenylamine, dicyclohexyl-amine, fluorene, and 1,2,3,4,4a,9a-hexahydrofluorene were synthesized. The bis(2-dimethylaminoethyl) derivative of fluorene was also obtained. All of these compounds were tested for antihistaminic and antimus-carinic activity in isolated guinea pig ileum. The compounds showed only non-competitive antimuscarinic activity which was probably due to a non-specific toxic effect. All of the compounds showed competitive antihistaminic activity. The fully hydrogenated compounds and the di-substituted fluorene derivative showed non-competitive antihistaminic activity, again probably due to a non-specific toxic effect, as well as weak competitive antagonism. The seven aromatic or indolic compounds showed a high degree of competitive activity. These compounds, followed by the pA₂ values, were: 5-(2-dimethylaminoethyl)-5,6,7,8,9,10-hexahydrocyclohept[b] indole (7.94), 9-(2-dimethylaminoethyl)-1,2,3,4,4a,9a-hexahydrofluorene (7.45), 9-(2-dimethylaminoethyl)-1,2,3,4-tetrahydrocarbazole (6.90), N-(2-di-methylaminoethyl)diphenylamine (6.67), 9-(2-dimethylaminoethyl)carbazole (6.38), 9-(2-dimethylaminoethyl)fluorene (6.12), and 4-(2-dimethylamino-ethyl)-1,2,3,4-tetrahydrocyclopent[b] indole (6.12). The pA₂ value for diphenhydramine was found to be 7.75. The results are discussed in terms of the steric nature and possible binding modes of the antihistaminic receptor.

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