A new synthesis of the ORL-1 antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) and activity in a calcium mobilization assay.
A new chiral synthesis of the ORL-1 antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (2, J-113397) was developed. J-113397 has a K(e)=0.85nM in an ORL-1 calcium mobilization assay and is 89-, 887-, and 227-fold selective for the ORL-1 receptor relative to the mu, delta, and kappa opioid receptors.
Smith
Emilie D
ED
Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709, USA.
Ariane Vinson
N
N
Zhong
Desong
D
Berrang
Bertold D
BD
Catanzaro
Jennifer L
JL
Thomas
James B
JB
Navarro
Hernán A
HA
Gilmour
Brian P
BP
Deschamps
Jeffrey
J
Carroll
F Ivy
FI
D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D008968:Molecular Conformation; D015394:Molecular Structure; D009292:Narcotic Antagonists; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011957:Receptors, Opioid; D013237:Stereoisomerism; D000094942:Nociceptin Receptor
D001562:Benzimidazoles; C402921:J 113397; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; D002118:Calcium; D000094942:Nociceptin Receptor; C000722283:OPRL1 protein, human