SCREENING OF NOVEL ISOINDOLE LEAD COMPOUNDS AND DETERMINATION MECHANISM OF ACTION OF MOST ACTIVE ONES ON ISOLATED RABBIT INTESTINE

EI-Hadiyah TM, Madani AM*, Ahmed Aimum, Talal Elsaman and Hatem A. Abdel-Aziz

ABSTRACT

Background: Isoindole derivatives were rich source for numerous useful drugs and attract new drug discovery seekers. Objectives: The purpose of the study was to investigate the contracting effect of three newly synthesized isoindole derivatives (TIND-1, 10, and 11) on isolated rabbit intestine preparations, in vitro, moreover elucidating of the possible mechanism of action for the most active compound was carried out. Methods: The three tested compounds and standards agonists; acetylcholine, 5HT and barium chloride in concentration range of (10-5-10-10M) were used during the experiments, whilst standard antagonists; atropine and cyproheptadine were used only in two concentrations low (10-10M) and high (10-8M). Using organ bath, dose response curves of tested compounds alone and in the presence of their blockers in comparison to standards were constructed using cumulative dose cycle procedure on isolated rabbit intestine, in vitro. Results: The synthetic tested compounds TIND-1, TIND-10, TIND-11 demonstrated contracting effect on isolated rabbit intestine smooth muscle and TIND-1 showed the best profile. On other hand, TIND-1 had low efficacy upon comparison with standard spasmogen. Atropine in two different doses shifted the TIND-1 dose–response curve to right and downward, whilst cyproheptadine was without effect on TIND-1 dose-response curve. Conclusion: All the three tested compounds produced contracting effects on isolated rabbit intestine preparation and TIND-1 was the most promising one. TIND-1 mediates its contraction via muscurinic receptors. Further investigations are required to demonstrate other mechanistic role(s) involved in this contracting effect such as ion channels or prostaglandin receptors.

Keywords: TIND-1, TIND-10, TIND-11, Isoindole, Rabbit intestine, Madani.