Synthesis and Octopaminergic-agonist Activity of 2-(Arylimino)thiazolidines, 2-(Aralkylamino)-2-thiazolines, and Related Compounds

2-(Arylimino)thiazolidines (AITs) were synthesized by cyclizing monoethanolamine hydrogen sulfate with arylisothiocyanates in the presence of sodium hydroxide, or by the hydrochloric acid-catalyzed cyclization of thiourea. 2-(Aralkylamino)-2-thiazolines (AATs) and thiazines were obtained by the hydrochloric acid-catalyzed cyclization of the corresponding thioureas. 2-(2, 6-Diethylphenylimino)oxazolidine was obtained by cyclodesulfurizing the corresponding thiourea with yellow mercuric oxide. The activity for stimulating adenylate cyclase prepared from ventral nerve cords of the American cockroach Periplaneta americana L. by these compounds was examined at 100 μM. AIT with a 2, 6-diethylphenyl group was more active than its oxazolidine derivative. Greater enzyme activation appeared to result from short-chain alkyl rather than halogen substitution at the 2, 6-positions of the aromatic ring of AITs. Increasing the chain length from methyl to ethyl in 2, 6-disubstituted AIT caused an increase in the enzyme activation. There was a marked decrease in the enzyme activation after alkylating the ring nitrogen or C₅, and after ring expansion of potent AIT and AAT. Thus, a certain degree of bulkiness and hydrophobicity at the 2- and 6-positions on the phenyl ring of AIT and at the N-terminal of AIT and AAT were favorable for activating the adenylate cyclase.