5-HT_4A Receptor ( pKi = 8.6 ); 5-HT_4B Receptor ( pKi = 8.1 )

Thirty-nine percent of patients receiving 2 mg of Prucalopride and twenty-eight percent of those receiving 4 mg reported having a complete bowel movement every week, compared to twelve percent of the placebo group. The average number of spontaneous, full bowel movements increased by one or more per week in 47.3% of patients receiving 2 mg of prucalopride and 46.6% of patients receiving 4 mg of the medication, compared to 25.8% in the placebo group. All other secondary efficacy end points, such as patient satisfaction with bowel function and treatment and their assessment of the severity of their constipation symptoms, are significantly improved by prucalopride (2 mg or 4 mg).[2] Those taking prucalopride at doses of 2 mg (19.5%) or 4 mg (23.6%) had higher rates of three or more spontaneous complete bowel movements (SCBM) per week than those taking a placebo (9.6%). Secondary efficacy and quality of life endpoints, such as the percentage of patients experiencing an increase of one or more SCBM/week, the completion of evacuation, the perceived severity of the disease, the efficacy of treatment, and quality of life, are also markedly enhanced by prracalopride.[4] The effects of pruricalopride on colonic contractile motility patterns are dose-dependent. In dogs that are fasting, it stimulates high-amplitude clustered contractions in the proximal colon and inhibits contractile activity in the distal colon. The time until the first giant migrating contraction (GMC) is also lowered by prucalopride in a dose-dependent manner; at higher doses, the first GMC typically happens within the first 30 minutes following treatment.[5]

Prucalopride is the first member of the benzofuran class and a novel enterokinetic compound. Our goal was to determine its pharmacological profile through a range of organ bath and receptor binding experiments. With mean pK(i) estimates of 8.60 and 8.10 for the human 5-HT(4a) and 5-HT(4b) receptors, respectively, receptor binding data have shown prucaloprides high affinity to both investigated 5-HT(4) receptor isoforms. Only the human D(4) receptor (pK(i) 5.63), the mouse 5-HT(3) receptor (pK(i) 5.41) and the human sigma(1) (pK(i) 5.43) have demonstrated measurable affinity from the 50 other binding assays examined in this study, resulting in at least 290-fold selectivity for the 5-HT(4) receptor. Classical organ bath experiments were performed using different protocols on isolated gastrointestinal tract tissues from rats, guinea pigs, and dogs. In the guinea-pig colon, prucalopride was a 5-HT(4) receptor agonist because it caused contractions (pEC(50)=7.48+/-0.06; insensitive to a 5-HT(2A) or 5-HT(3) receptor antagonist, but inhibited by a 5-HT(4) receptor antagonist) and promoted noncholinergic contractions induced by electrical stimulation (blocked by a 5-HT(4) receptor antagonist). In addition, it resulted in the 5-HT(4) receptor antagonist-sensitive relaxation of a rat oesophagus preparation (pEC(50)=7.81+/-0.17). Up to 10 microM, pracilocapride did not significantly inhibit the contractions mediated by the 5-HT(2A), 5-HT(2B), or 5-HT(3) receptors, motilin or cholecystokinin (CCK(1)) receptors, or nicotinic or muscarinic acetylcholine receptors. In summary, prucalopride is a strong, particular, and selective 5-HT(4) receptor agonist. It is significant to note that prucalopride does not impede the actions of 5-HT(2A), 5-HT(2B), and 5-HT(3) receptors, motilin, or CCK(1) receptors, and is not anti-cholinergic, anticholinesterase, or nonspecific inhibitory activity. This is important because the drug is intended to treat disorders related to intestinal motility.

Classical organ bath experiments were performed using different protocols on isolated gastrointestinal tract tissues from rats, guinea pigs, and dogs. In the guinea-pig colon, prucalopride was a 5-HT(4) receptor agonist because it caused contractions (pEC(50)=7.48+/-0.06; insensitive to a 5-HT(2A) or 5-HT(3) receptor antagonist, but inhibited by a 5-HT(4) receptor antagonist) and promoted noncholinergic contractions induced by electrical stimulation (blocked by a 5-HT(4) receptor antagonist). In addition, it resulted in the 5-HT(4) receptor antagonist-sensitive relaxation of a rat oesophagus preparation (pEC(50)=7.81+/-0.17).

Sprague dawley rats (diabetes mellitus (DM) model)
5 or 10 µg/kg
Oral gavage; single daily for 2 weeks.

[1]. Eur J Pharmacol . 2001 Jun 29;423(1):71-83.

[2]. N Engl J Med . 2008 May 29;358(22):2344-54.

[3]. Gastroenterology . 2001 Feb;120(2):354-60.

[4]. Gut. 2009 Mar;58(3):357-65.

[5]. Neurogastroenterol Motil . 2001 Oct;13(5):465-72.

C18H26CLN3O3

367.87

367.17

C, 58.77; H, 7.12; Cl, 9.64; N, 11.42; O, 13.05

179474-81-8

Prucalopride succinate; 179474-85-2; Prucalopride-13C,d3; 2140306-00-7; Prucalopride hydrochloride; 179474-80-7; 179474-85-2 (Succinate)

Solid powder

COCCCN1CCC(CC1)NC(=O)C2=CC(=C(C3=C2OCC3)N)Cl

ZPMNHBXQOOVQJL-UHFFFAOYSA-N

InChI=1S/C18H26ClN3O3/c1-24-9-2-6-22-7-3-12(4-8-22)21-18(23)14-11-15(19)16(20)13-5-10-25-17(13)14/h11-12H,2-10,20H2,1H3,(H,21,23)

4-amino-5-chloro-N-[1-(3-methoxypropyl)piperidin-4-yl]-2,3-dihydro-1-benzofuran-7-carboxamide

Prucalopride free base; R 093877; R-093877; R093877; R-108512; R 108512; R108512; R-93877; R93877； Prucalopride; Motegrity; Resolor; Resotran; R 93877

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: 50 mg/mL (135.92 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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Solubility in Formulation 2: ClC1=C(N)C(CCO2)=C2C(C(NC3CCN(CCCOC)CC3)=O)=C1

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 (Please use freshly prepared in vivo formulations for optimal results.)