Conformationally constrained o-tolylpiperazine camphorsulfonamide oxytocin antagonists. Structural modifications that provide high receptor affinity and suggest a bioactive conformation

• Published in: Bioorganic & medicinal chemistry Vol. 2; no. 9; pp. 971 - 985
• Main Authors: Williams, Peter D., Ball, Richard G., Clineschmidt, Bradley V., Culberson, J.Chris, Erb, Jill M., Freidinger, Roger M., Pawluczyk, Joseph M., Perlow, Debra S., Pettibone, Douglas J., Veber, Daniel F.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.09.1994
• Subjects: Amino Acid Sequence; Animals; Camphor - analogs & derivatives; Camphor - chemistry; Camphor - pharmacology; Female; Humans; Kidney - metabolism; Kinetics; Liver - metabolism; Male; Models, Molecular; Molecular Conformation; Molecular Sequence Data; Oxytocin - antagonists & inhibitors; Oxytocin - metabolism; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Rats; Receptors, Oxytocin - antagonists & inhibitors; Receptors, Oxytocin - metabolism; Receptors, Vasopressin - drug effects; Receptors, Vasopressin - metabolism; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Tritium; Uterine Contraction - drug effects; Uterus - metabolism
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(00)82046-5

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-V 1a 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. A series of novel o-tolylpiperazine camphorsulfonamide oxytocin antagonists containing rotationally restricted 1-acylamino-2-propyl substituents at the C2- endo position on camphor is described.