Antispasmodic activity of xanthoxyline derivatives: structure-activity relationships.
The antispasmodic activity of several xanthoxyline derivatives against acetylcholine-induced contraction of the guinea pig ileum was evaluated in vitro. The acetophenones with two methoxyl groups, mainly in the 3,4 positions, exhibited potent antispasmodic activity. Modification of the hydroxyl group in xanthoxyline by the introduction of benzoyl, acetyl, or tosyl groups produced inactive compounds, whereas the introduction of benzyl or p-methoxybenzyl groups furnished compounds that were four- to eight-fold more potent than xanthoxyline. In marked contrast, the introduction of a methyl group gave a compound that caused contractant activity. Modification of the carbonyl group of xanthoxyline lead to inactive compounds, whereas the condensation of xanthoxyline with benzaldehydes gave chalkones that were about fivefold more potent than xanthoxyline. The introduction of benzyl and styrene groups, on the basis of the similarity with papaverine, improves the antispasmodic action of the xanthoxyline derivates. Our results suggest that the methoxyl and carbonyl groups are critical structural points for the antispasmodic activity of xanthoxyline derivatives. The hydroxyl group improves antispasmodic activity, but is not fundamental to its manifestation.
Cechinel Filho
V
V
Departamento de Química, Universidade Federal de Santa Catarina, Brazil.
Miguel
O G
OG
Nunes
R J
RJ
Calixto
J B
JB
Yunes
R A
RA
D000098:Acetophenones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010276:Parasympatholytics / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology*; D010946:Plants, Medicinal / Q000737:chemistry; D013329:Structure-Activity Relationship
D000098:Acetophenones; D010276:Parasympatholytics; D000109:Acetylcholine; C064382:xanthoxyline