title: Synthesis and Octopaminergic-agonist Activity of 3-(Substituted Phenyl)imidazolidine-2-thiones and Related Compounds.
abstract: 3-(Substituted phenyl)imidazolidine-2-thiones (SPITs) and related compounds were synthesized by cyclizing monoethanolamine hydrogen sulfate with arylisothiocyanates in the presence of sodium hydroxide. The activity for stimulating adenylate cyclase prepared from thoracic nerve cords of the American cockroach, Periplaneta americana L., was examined with these compounds. A SPIT with a 2,6-diethylphenyl group (48) was the only full agonist, the other SPIT derivatives being partial agonists. Greater enzyme activation appeared to result from short-chain alkyl rather than halogen substitution at the 2,6-positions of the aromatic ring of SPITs. Increasing the chain length from methyl to ethyl in 2,6-disubstituted SPIT caused an increase in the enzyme activation. Meanwhile, further increase of the chain length from ethyl to isopropyl in 2,6-disubstituted SPIT caused a decrease in the enzyme activation. Superimposition of energy-minimized octopamine and 48 revealed structural and conformational similarities that account for the higher Vmax value of 48. There was a marked decrease in the enzyme activation after alkylating at C4 or C5 of the imidazolidine ring of the potent SPITs. Thus, a certain degree of bulkiness and hydrophobicity at the 2- and 6-positions on the phenyl ring of a SPIT and the N-terminal was favorable for activating adenylate cyclase.
authors.affiliation: a Department of Agricultural Chemistry, Kyushu University.
authors.forename: A
authors.initials: A
authors.lastname: Hirashima
authors.affiliation: a Department of Agricultural Chemistry, Kyushu University.
authors.forename: K
authors.initials: K
authors.lastname: Shinkai
authors.affiliation: a Department of Agricultural Chemistry, Kyushu University.
authors.forename: E
authors.initials: E
authors.lastname: Kuwano
authors.affiliation: a Department of Agricultural Chemistry, Kyushu University.
authors.forename: E
authors.initials: E
authors.lastname: Taniguchi
authors.affiliation: a Department of Agricultural Chemistry, Kyushu University.
authors.forename: M
authors.initials: M
authors.lastname: Eto
keywords: 3-(substituted phenyl)imidazolidine-2-thiones; Periplaneta americana; adenylate cyclase; molecular modeling; octopaminergic agonist