Identification of a series of 3-(benzyloxy)-1-azabicyclo[2.2.2]octane human NK1 antagonists.

The synthesis and in vitro and in vivo evaluation of a series of 3-(benzyloxy)-1-azabicyclo-[2.2.2]octane NK1 antagonists are described. While a number of 3,5-disubstituted benzyl ethers afford high affinity, the 3,5-bis(trifluoromethyl)benzyl was found to combine high in vitro affinity with good oral activity. Detailed structure-activity relationship studies in conjunction with data from molecular modeling and mutagenesis work have allowed the construction of a model of the pharmacophore. Specific interactions that have been identified include an interaction between His-197 and one of the rings of the benzhydryl, a lipophilic pocket containing His-265 that the benzyl ether occupies, and a possible hydrogen bond between Gln-165 and the oxygen of the benzyl ether.

Radioiodinated L-703,606: a potent, selective antagonist to the human NK1 receptor.

A new, radioiodinated, NK1 selective radiotracer ([125I]L-703,606) was prepared. L-703,606 is an iodinated analog of the NK1 antagonist CP-96,345 in which the methoxy group has been replaced by an iodine substituent. [125I]L-703,606 was made from the corresponding trimethylsilyl compound by treatment with no carrier added Na 125I and an Iodobead in TFA. The tracer was prepared at a specific activity of approx. 1100 Ci/mmol and preliminary binding studies demonstrated that [125I]L-703,606 binds selectively to NK1 receptors with a kd = 0.3 nM. These results suggest that this radioligand will be useful for the biochemical and pharmacological characterization of the human NK1 receptor and, if labeled with I-123, may be useful for non-invasive NK1 receptor imaging via SPECT.

7-Methoxybenzofuran-4-carboxamides as PDE 4 inhibitors: a potential treatment for asthma.

The synthesis and pharmacological profile of a novel series of 7-methoxybenzofuran-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4).