Four 2-alkyl (methyl, ethyl, n-propyl and isopropenyl) analogues of
idazoxan (
RX 781094) have been synthesized and assessed in terms of their central alpha 2/alpha 1-adrenoceptor selectivity and alpha 2-adrenoceptor antagonist potency using both in vitro and in vivo tests in the rat. In cortical binding assays using [3H]-
idazoxan and [3H]-
prazosin,
idazoxan had a 5 times greater alpha 2/alpha 1-selectivity than
yohimbine. The 2-alkyl substituted analogues all showed improved selectivity, being between 17 and 29 times more selective than
yohimbine for [3H]-
idazoxan binding sites. In terms of central antagonist potency in vivo, the most favourable substitutions were 2-ethyl (
RX 811033) and 2-n-propyl (RX 811054). Compared with
yohimbine, these analogues were, respectively, 36 and 18 times more potent intravenously and 5 and 7.5 times more potent orally in their antagonism of
guanoxabenz-induced
mydriasis in the
pentobarbitone-anaesthetized rat. All the analogues had a duration of action similar to that of
idazoxan, which was significantly shorter than that of
yohimbine. The results indicate that introduction of alkyl groups in the 2-position of
idazoxan greatly increases the alpha 2/alpha 1-adrenoceptor selectivity as measured in binding studies. Improved alpha 2-adrenoceptor affinity and antagonist potency were particularly associated with the 2-ethyl and 2-n-propyl analogues.