SYNTHESIS AND 5-HT-3 RECEPTOR-BINDING ACTIVITY OF DIMETHOXY-N-(1-AZABICYCLO[2.2.2]OCT-3-YL)BENZAMIDE AND ITS 5-HALOGEN-2-ALKOXYL HOMOLOGS

dimethoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide (MIZAC) was prepare d from 5-iodo-2,3-dimethoxybenzoyl chloride and (S)-3-aminoquinuclidin e. [I-125]Iodode-stannylation of its corresponding 5-tri-n-butyltin de rivative gave [I-125]-MIZAC at 1800 Ci/mmol. Binding of [I-125]-MIZAC in rat entorhinal cortex revealed a K-D of 1.37 +/- 0.21 nM. A series of racemic 2-O-alkyl derivatives of MIZAC were prepared and 5-HT-3 rec eptor affinities were determined by inhibition of [I-125]-MIZAC bindin g. Optimal affinity for the receptor was obtained with small, electron -withdrawing substituents in the aromatic 5-position and with bulky su bstituents in the 3-position. [I-125]-MIZAC is a selective radioligand useful for in vitro identification of the 5-HT-3 receptor.