SYNTHESIS AND OCTOPAMINERGIC-AGONIST ACTIVITY OF 3-(SUBSTITUTED PHENYL)IMIDAZOLIDINE-2-THIONES AND RELATED-COMPOUNDS

3-(Substituted phenyl)imidazolidine-2-thiones (SPITs) and related comp ounds were synthesized by cyclizing monoethanolamine hydrogen sulfate with arylisothiocyanates in the presence of sodium hydroxide. The acti vity for stimulating adenylate cyclase prepared from thoracic nerve co rds of the American cockroach, Periplaneta americana L., was examined with these compounds. A SPIT with a 2,6-diethylphenyl group (48) was t he only full agonist, the other SPIT derivatives being partial agonist s. 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. Mean while, further increase of the chain length from ethyl to isopropyl in 2,6-disubstituted SPIT caused a decrease in the enzyme activation, Su perimposition of energy-minimized octopamine and 48 revealed structura l and conformational similarities that account for the higher Vmax val ue of 48. There was a marked decrease in the enzyme activation after a lkylating at C-4 or C-5 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 favora ble for activating adenylate cyclase.