title: Conformationally constrained o-tolylpiperazine camphorsulfonamide oxytocin antagonists. Structural modifications that provide high receptor affinity and suggest a bioactive conformation.
abstract: A series of new o-tolylpiperazine camphorsulfonamide OT antagonists is described. Analogs containing conformationally constrained 1-acylamino-2-propyl substituents at the camphor C2 endo position exhibit high affinity for OT and AVP-V1a receptors or high affinity and selectivity for OT receptors, depending on functionalities present in the acyl group. Determination of the preferred conformation of potency-enhancing 1-acylamino-2-propyl substituents using molecular mechanics energy calculations and X-ray crystallography, along with topological similarities to a conformationally constrained cyclic hexapeptide OT antagonist, suggests a receptor-bound conformation for this series of non-peptide OT antagonists.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486.
authors.forename: P D
authors.initials: PD
authors.lastname: Williams
authors.forename: R G
authors.initials: RG
authors.lastname: Ball
authors.forename: B V
authors.initials: BV
authors.lastname: Clineschmidt
authors.forename: J C
authors.initials: JC
authors.lastname: Culberson
authors.forename: J M
authors.initials: JM
authors.lastname: Erb
authors.forename: R M
authors.initials: RM
authors.lastname: Freidinger
authors.forename: J M
authors.initials: JM
authors.lastname: Pawluczyk
authors.forename: D S
authors.initials: DS
authors.lastname: Perlow
authors.forename: D J
authors.initials: DJ
authors.lastname: Pettibone
authors.forename: D F
authors.initials: DF
authors.lastname: Veber
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002164:Camphor / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010121:Oxytocin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D017483:Receptors, Vasopressin / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014316:Tritium; D014590:Uterine Contraction / Q000187:drug effects; D014599:Uterus / Q000378:metabolism
chemical_list: D010879:Piperazines; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; D013449:Sulfonamides; D014316:Tritium; D010121:Oxytocin; D002164:Camphor