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2‐Alkyl analogues of idazoxan (RX 781094) with enhanced antagonist potency and selectivity at central α 2 ‐adrenoceptors in the rat
Author(s) -
Gadie B.,
Lane A.C.,
McCarthy P.S.,
Tulloch I.F.,
Walter D.S.
Publication year - 1984
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1984.tb16224.x
Subject(s) - idazoxan , yohimbine , antagonist , prazosin , chemistry , potency , in vivo , selectivity , stereochemistry , rauwolscine , alpha (finance) , antagonism , pharmacology , in vitro , biology , receptor , biochemistry , medicine , microbiology and biotechnology , catalysis , construct validity , nursing , patient satisfaction
1 Four 2‐alkyl (methyl, ethyl, n ‐propyl and isopropenyl) analogues of idazoxan (RX 781094) have been synthesized and assessed in terms of their central α 2 /α 1 ‐adrenoceptor selectivity and a 2 ‐adrenoceptor antagonist potency using both in vitro and in vivo tests in the rat. 2 In cortical binding assays using [ 3 H]‐idazoxan and [ 3 H]‐prazosin, idazoxan had a 5 times greater α 2 /α 1 ‐selectivity than yohimbine. The 2‐alkyl substituted analogues all showed improved selectivity, being between 17 and 29 times more selective than yohimbine for [ 3 H]‐idazoxan binding sites. 3 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. 4 All the analogues had a duration of action similar to that of idazoxan, which was significantly shorter than that of yohimbine. 5 The results indicate that introduction of alkyl groups in the 2‐position of idazoxan greatly increases the α 2 /α 1 ‐adrenoceptor selectivity as measured in binding studies. Improved α 2 ‐adrenoceptor affinity and antagonist potency were particularly associated with the 2‐ethyl and 2‐ n ‐propyl analogues.