781662-47-3Relevant articles and documents
Rationale, design, and synthesis of novel phenyl imidazoles as opioid receptor agonists for gastrointestinal disorders
Breslin, Henry J.,Miskowski, Tamara A.,Rafferty, Bryan M.,Coutinho, Santosh V.,Palmer, Jeffrey M.,Wallace, Nathaniel H.,Schneider, Craig R.,Kimball, Edward S.,Zhang, Sui-Po,Li, Jian,Colburn, Raymond W.,Stone, Dennis J.,Martinez, Rebecca P.,He, Wei
, p. 5009 - 5020 (2007/10/03)
A small series of novel, imidazoles 4 have been prepared that exhibit very good binding affinities for the δ and μ opioid receptors (ORs), as well as demonstrate potent agonist functional activity at the δ OR. Representative imidazole 4a (Ki δ = 0.9 nM; Ki μ = 55 nM; Ki K = 124 nM; EC50 δ =13-25 nM) was further profiled for OR related in vivo effects. Compound 4a reduced gastrointestinal (GI) propulsive motility in a dose-dependent and naloxone-reversible manner, based on the results of the mouse glass bead expulsion test (3, 5, and 10 mg/kg, ip) and the mouse fecal pellet output test (1 and 3 mg/kg, ip). Compound 4a showed no analgesic activity as measured by the mouse abdominal irritant test (MAIT) when dosed at 100 mg/kg, sc, but did show significant MAIT activity at doses of both 10 μg (40% inhibition) and 100 μg (100% inhibition) when dosed intracerebroventricularly (icv). Taken together, these in vivo results suggest that 4a acts peripherally when dosed systemically, and that these prototypical compounds may prove promising as medicinal leads for GI indications.
