Potential neuroleptic agents. 3. Chemistry and antidopaminergic properties of substituted 6-methoxysalicylamides

• Published in: Journal of medicinal chemistry Vol. 28; no. 9; pp. 1263 - 1269
• Main Authors: De Paulis, Tomas, Kumar, Yatendra, Johansson, Lars, Raemsby, Sten, Florvall, Lennart, Hall, Haakan, Aengeby-Moeller, Kristina, Oegren, Sven Ove
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01-09-1985
• Subjects: Animals; Apomorphine; Benzamides; Chemical Phenomena; Chemistry; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Dopamine Antagonists; Humans; Hyperkinesis - chemically induced; Hyperkinesis - drug therapy; Magnetic Resonance Spectroscopy; Male; Rats; Rats, Inbred Strains; Salicylamides - chemical synthesis; Salicylamides - pharmacology; Salicylamides - therapeutic use; Spiperone - metabolism; Stereotyped Behavior - drug effects; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00147a025

A series of substituted 6-methoxysalicylamides were synthesized from their corresponding 2,6-dimethoxybenzamides by demethylation of one methoxy group with boron tribromide. Substituted 6-methoxysalicylamides having a lipophilic aromatic substituent in the 3-position para with respect to the methoxy group, e.g. a bromo or an iodo atom or an ethyl or a propyl group, and having an (S)-N-(1-alkyl-2-pyrrolidinyl)methyl moiety as the side chain were found to be potent blockers of [3H]spiperone binding in vitro and potent inhibitors of the apomorphine syndrome in the rat. Similar to remoxipride but in contrast to haloperidol, some of the substituted salicylamides show a 10-20-fold separation between the dose that inhibits hyperactivity and that which inhibits stereotypy. It was concluded that, besides the requirement of a lipophilic substituent in the position para to the methoxy group for antidopamine activity in vivo, the formation of a coplanar six-membered pseudoring involving the amide moiety and the methoxy group is a structural requirement for activity in vitro.