Прукалоприд

Prucalopride is a potent and selective agonist of the serotonin (5-HT) receptor subtype 5-HT₄ (K_is = 2.5 and 8 nM for human 5-HT_4A and 5-HT_4B, respectively). Prucalopride is greater than 250-fold selective for 5-HT₄ over a panel of 53 overexpressed receptors, including 5-HT subtypes, but does bind to human dopamine D₄ and sigma-1 (σ₁) receptors and mouse 5-HT₃ receptors (K_is = 2.3, 3.7, and 3.8 μM, respectively). It induces contractions in guinea pig colon with an EC₅₀ value of 33 nM, an effect that is blocked by the 5-HT₄ antagonist GR113808 but not the 5-HT_2A and 5-HT₃ antagonists ketanserin and granisetron , respectively. It also facilitates non-cholinergic contractions induced by electrical stimulation. In fasted dogs, oral administration of prucalopride increases colonic motility by inhibiting distal colon contractions (ED₅₀ = 0.04 mg/kg), an effect that is blocked by pretreatment with the 5-HT₄ antagonist GR125487. Prucalopride (5-10 mg/kg, s.c.) increases acetylcholine and histamine levels in the rat prefrontal cortex by 2.4-fold and 3-fold, respectively, and increases the power of hippocampal theta oscillations. Formulations containing prucalopride have been used in the treatment of chronic idiopathic constipation.

In healthy male individuals, prucalopride decreases the display of esophageal acid and promotes gastric emptying. It is effective, safe and shows good tolerance for the treatment of men with chronic constipation.

Prucalopride is a high affinity, highly selective 5-HT4 agonist. Its action in the treatment of chronic constipation is to stimulate intestinal peristalsis by specifically interacting with 5-HT4 receptors in the digestive tract, resulting in the release of acetylcholine, which further constricts the muscular layer of the colon, and the relaxation of the circular muscular layer promoting the expulsion of luminal contents.

This novel enterokinetic drug (FW = 367.87 g/mol; CAS 179474-81-8), also known by the tradename Resolor? and its systematic name, 4-amino-5- chloro-N-[1-(3-methoxypropyl)piperidin-4-yl]-2,3-dihydro-1-benzofuran-7- carboxamide, is a selective, high affinity serotonin 5-HT4 receptor agonist with that stimulates colonic mass movements, which provide the main propulsive force for defecation. It exhibits high affinity to both 5-HT4 receptor isoforms, with respective pKi values of 8.60 and 8.10 for the human 5-HT4A and 5-HT4B receptors. Based on 50 other binding assays,tonly the human D4 receptor (pKi = 5.63), the mouse 5-HT3 receptor (pKi = 5.41) and the human s1 (pKi = 5.43) shown measurable affinity, resulting in >290x selectivity for 5-HT4 receptors. Prucalopride also differs from other 5-HT4 agonists, such as tegaserod and cisapride, that interact with other receptors (5-HT1B/D and cardiac human ether-a-go-go K+ or hERG channel, respectively).