Basel Abdel-Wahab

In this study, we tested the effect of urocortin 1 (Ucn1) on the contractility of gallbladder smooth muscle (GBSM) strips from guinea pigs and studied the involvement of corticotropin-releasing factor (CRF) receptors in this effect. The effect of Ucn1 on the isometric contractions of non-contracted and acetylcholine (Ach)-contracted GBSM, and the effects of CRF-R antagonists antalarmin and astressin 2B on the effect of Ucn1 were studied. In addition, the expression of receptors for CRF-R1 and CRF-R2 in guinea pig gallbladder were investigated using reverse transcription - polymerase chain reaction (RT-PCR). Ucn1 dose-dependently inhibited the contractility of GBSM. Moreover, Ucn1 decreased the resting tension, the mean contractile amplitude, and the contractile frequency in both non-contracted and Ach-contracted strips of GBSM. Furthermore, Ucn1 induced rightward shift of the Ach concentration-response curve of Ach in Ach-contracted strips. This inhibitory effect of Ucn1 on both non-contracted and Ach-contracted strips was inhibited by astressin 2B, but not by antalarmin. RT-PCR demonstrated that the CRF-R2, but not CRF-R1 receptor subtype is expressed in the muscularis muscle of guinea pig gallbladder. In conclusion, Ucn1 has an inhibitory effect on the contractility of GBSM of guinea pig, mediated through stimulating CRF-R2 receptors in GBSM. More studies are needed to clarify the intracellular signaling events involved in this effect.

In trials to preserve the pharmacological profile and improve the bioavailability via lipophilicity increment of baclofen 1 and searching for more potent and less toxic muscle relaxants and analgesics, nine substituted cyclic analogues of 1 were designed and synthesized. The target derivatives 5-(4-chlorophenyl)-5,6-dihydro-1,3-oxazepin-7(4H)-one (11-19) were obtained through amide formation to the corresponding intermediates (2-10) followed by cyclization using acetic anhydride. The structures of the target compounds (11-19) were confirmed by IR, (1)H NMR, MS, and elemental analyses. The neuropharmacological activities of these lipophilic cyclic analogues (11-19) were assessed for their effects on motor activity, muscle relaxation, pain relief and impaired cognition, by intraperitoneal administration at a dose of 3mg/kg with reference to those of baclofen 1. Our results showed that compounds 11-14 are devoid of all of the tested pharmacological effects associated with 1. In all paradigms tested, undecyl, tridecyl, heptdec-8-enyl and benzyl substituted analogue derivatives (15, 16, 18, and 19) revealed a significant neurological activity being vividly favorable comparable with baclofen 1. 2-Benzyl-5-(4-chlorophenyl)-5,6-dihydro-1,3-oxazepin-7(4H)-one derivative 19 is the most active candidate with high significant neurological potencies, while 5-(4-chlorophenyl)-2-(dec-8-enyl)-5,6-dihydro-1,3-oxazepin-7(4H)-one derivative 17 displayed activity at relatively higher time interval. These results probe a new structurally distinct class incorporating 1,3-oxazepine nucleus as promising candidates as GABA(B) agonists for further investigations.