Synthesis and structure-activity relationships of CP-122,721, a second-generation NK-1 receptor antagonist.

The synthesis and SAR of benzylamine side chain analogs of the NK-1 receptor antagonist CP-99,994 are described. The 5-trifluoromethoxy analog, CP-122,721, shows superior in vivo blockade of NK-1 receptor mediated responses.

Design of novel cholecystokinin-B receptor ligands based on the 'double-ring system' approach.

A structurally novel series of cholecystokinin-B (CCK-B) receptor ligands has been designed and synthesized based on the 'double ring system' theory of receptor recognition. Compounds 2b-cis and 2g-cis from this 1-amino-2-benzyltetralin series show modest CCK-B receptor affinity, with IC50 values of 48.5 nM and 39.0 nM, respectively. The results are discussed in the context of ongoing efforts to identify the CCK-B receptor binding site for nonpeptide ligands.

Characterization of CP-122,721; a nonpeptide antagonist of the neurokinin NK1 receptor.

CP-122,721 [(+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2 -phenylpiperidine] interacts with high affinity (pIC50 = 9.8) at the human NK1 receptor expressed in IM-9 cells. In the presence of CP-122,721, there was a reduction in Bmax of [125I]BH-SP binding with no change in affinity suggesting that CP-122,721 does not interact with the NK1 receptor in competitive manner. In an in vitro functional assay. CP-122,721 blocked SP-induced excitation of locus ceruleus cells in guinea pig brain slices with a IC50 value of 7 nM. In vivo, CP-122,721 potently blocked plasma extravasation in guinea pig lung elicited by aerosolized capsaicin (1 mM) with an ID50 = 0.01 mg/kg, p.o. Orally administered CP-122,721 antagonized Sar9, Met (O2)11-SP-induced locomotor activity in guinea pigs with an ID50 = 0.2 mg/kg suggesting good entry into the central nervous system. In addition, consistent with insurmountable blockade observed in vitro, CP-122,721 (0.01, 0.03 0.3 mg/kg, p.o.) produced a rightward shift in the dose response curve for SP-induced hypotension in the awake dog that was accompanied by a decrease in the maximal response. Thus, in vitro and in vivo CP-122,721 appears to behave functionally as a non-competitive antagonist producing an insurmountable blockade of the actions of SP.

5-Phenyl-3-ureidobenzazepin-2-ones as cholecystokinin-B receptor antagonists.

A series of 5-phenyl-3-ureidobenzazepin-2-one cholecystokinin-B (CCK-B) receptor antagonists was synthesized using Beckmann ring expansion of a suitable 4-phenyl-1-tetralone as a key step. Structure-activity relationship studies revealed the importance of the 5-phenyl group for potent and selective CCK-B affinity. Addition of an 8-methyl substituent and resolution provided the potent (CCK-B IC50 = 0.48 nM) CCK-B antagonist 4. The role of the 5-phenyl group as part of a "privileged structure" for high-affinity receptor antagonism is discussed.

Aza-tricyclic substance P antagonists.

The synthesis and structure-activity relationships of a series of aza-tricyclic analogs of the quinuclidine substance P (SP) antagonist 1 are described. The SP receptor affinity of these compounds was found to vary according to the size of the new ring fused to the quinuclidine and the mode of fusion. Correlations between receptor affinity and (1) the steric bulk of the newly introduced ring fusion and (2) the dihedral angle between the benzhydryl and benzylamino substituents of these aza-tricyclic compounds were explored.