VUF-8929

A new series of diphenylalkylamine congeners of prenylamine have been assayed in binding experiments on rat striatal membrane preparationsThe aim was to ascertain the influence of structural modifications and lipophilicity on their interaction with the [³H]tyramine-labeled vesicular transporter for dopamine.Thirteen compounds potently inhibited the specific binding of [³H]tyramine, with nanomolar K_i values in the range of those of established markers for the vesicular transporter of dopamine.Less lipophilic compounds displayed higher affinity for the energy-dependent amine transporter.

Potency and selectivity of currently available calmodulin (CaM) antagonists is rather limited.The authors attempted to improve the CaM-antagonistic activity in analogs of the CaM-antagonist prenylamine I (R¹-R⁵ = H, alkoxy, alkyl, halo; X-Y = ethanediyl, ethenediyl, etc.; n = 1-3; Z = methylene, alkanediyl, alkenediyl, etc.).The biol. test system used was the CaM-stimulated phosphodiesterase.Insertion of a double bond or heteroatoms (O, S) at the ring connecting C in the benzhydryl part of the mol. increases potency in comparison to prenylamine.Chain length is optimal with 4 atoms-nitrogen-3 atoms.Regarding benzhydryl substitution, halogenation results in a significantly increased improvement of CaM-inhibitory potency than methylation; p-substitution is superior to o-substitution.Secondary N seems to be advantageous as compared to tertiary amine.Lipophilicity was detected as a prime physicochem. descriptor of CaM-antagonistic potency.The role of lipophilicity, however, differs in a quant. sense when the subgroups are considered.It decreases within the subgroups in the following manner: saturated alkyl chain > double bond > S > O derivativesAmong the compounds described, new CaM antagonists with remarkably high potency were detected.