Ablukast

Molecular modeling studies were carried out by a combined use of conformational analysis and 3D-QSAR methods of identify molecular features common to a series of hydroxyacetophenone (HAP) and non-hydroxyacetophenone (non-HAP) peptide leukotriene (pLT) receptor antagonists. In attempts to develop a ligand-binding model for the pLT receptor, the Apex-3D program was used to identify biophoric structural patterns that are common to 13 diverse sets of compounds showing different levels of biological activity. A systematic conformational analysis was carried out to obtain sterically accessible conformations for these flexible compounds. Apex-3D was then utilized to propose common biophoric regions based on the selection of one of several conformations (MOPAC-minimized AM1) from each compound's data set that best fits the biophoric pattern and the resulting superimposition with all the other data-set compounds. Apex-3D identified three common biophoric features important for activity: one as the hydroxyl, acetyl, carbonyl and carboxyl groups, which mimic the acid-binding region of an agonist, the other as the hydrogen-bond donating site, and the third part is represented by a plane in which lipophilic aromatic groups align. The structure-activity relationships were then assessed by using the 3D-QSAR model. A common biophore model is proposed from the Apex-3D analysis which may be useful in designing new pLT antagonists. Molecular volumes and electrostatic potential similarities were also calculated in order to obtain the important structural requirements for the activity.

Although some leukotriene antagonists have been reported to block leukotriene (LT) C4responses in vivo, it is difficult to determine whether those antagonists block the effect of LTC4directly or act via blocking the action of LTD4, as LTC4is metabolized to LTD4rapidly in vivo. In this study, the dose–response curves of N-methyl LTC4(NMLTC4), the nonmetabolizable LTC4analogue, and the peptidoleukotrienes (LTC4, LTD4, and LTE4) were obtained in the absence and presence of the leukotriene antagonist Ro 23-3544 in cannulated frogs. The more potent effect of NMLTC4suggests that receptors that preferentially bind LTC4exist in frog vascular smooth muscle and the previously reported LTC4effect is a combination of LTC4and its less potent metabolite LTD4. The NMLTC4- and LTC4-induced hypotensive effects were antagonized by Ro 23-3544. Ro 23-3544 also antagonized the effects induced by high doses of LTD4and LTE4. Ro 23-3544 had no effect on duration of response and did not affect heart rate responses to LTC4at low dose of the antagonist. The data suggest that receptors that preferentially bind LTC4in bullfrog vascular smooth muscle regulate the hypotensive effect and that they can be antagonized by Ro 23-3544.Key words: leukotriene receptors, N-methyl LTC4, Ro 23-3544, cardiovascular, bullfrog.