Neural and molecular mechanisms in anxiety.

The recent discoveries of the benzodiazepine receptor and of antagonist compounds, such as beta-CCE, have advanced our understanding of the neurochemistry of anxiety. In this review we summarize the evidence implicating the benzodiazepine receptor in anxiety and relate this model to other models of anxiety.

Selectivity of benzodioxane alpha-adrenoceptor antagonists for alpha 1- and alpha 2-adrenoceptors determined by binding affinity.

A series of benzodioxane derivatives, structurally related to WB 4101 and piperoxan as well as prazosin and its two analogues UK-18,596 and UK-33,274, was studied with respect to their affinity for alpha 1-and alpha 2-adrenoceptors identified by 3H-prazosin (specific activity 33 Ci/mmol) and 3H-clonidine (specific activity 26.7 Ci/mmol), respectively, in isolated rat brain membranes. The structural variations made in these molecules gave rise to pronounced differences in affinity for alpha 1-adrenoceptors, whereas their binding affinity for alpha 2-adrenoceptors only slightly varied. Apart from piperoxan and its analogues, which showed some preference for alpha 2-adrenergic binding sites, all benzodioxane-like structures displayed a general selectivity for the alpha 1-adrenoreceptor sites labeled with 3H-prazosin. The drugs were 5-50 times more potent in inhibiting 3H-prazosin than 3H-clonidine from their specific binding sites in rat brain membranes. The highest alpha 1 selectivity was found for prazosin and UK-33,274. Within the present series of WB 4101-related benzodioxane compounds, the affinity for alpha 1-adrenoceptors is greatly reduced by alkyl substitution at the secondary amino nitrogen in the side chain. Ortho substitution of the phenyl moiety with methoxy increased affinity as did hydroxy at the para position. The side chain oxygen atom can be deleted or substituted by methylene without great loss in 3H-prazosin displacing effectiveness. The affinity for alpha 1-adrenoceptors was profoundly influenced by the configuration of the molecule. Upon introducing a second chiral center through a methyl group, the two resulting racemates differ 10-fold in activity and selectivity towards alpha 1-adrenoceptors. One of these racemates was even slightly more selective than WB 4101 itself. The selectivity of the drugs to bind to alpha 1-and alpha 2-adrenoceptors corresponded well with their in vivo selectivity to antagonize alpha 1- and alpha 2-adrenoceptor-mediated vasoconstriction in pithed normotensive rats. It is suggested that a systematic study of the structure-affinity relationship in benzodioxane antagonists may provide potent and selective blocking drugs of alpha 1-adrenoceptors.

Antagonist/agonist-preferring alpha-adrenoceptors or alpha 1/alpha 2-adrenoceptors?

Yohimbine and some stereoisomeric alkaloids inhibited the binding of 3H-clonidine and 3H-WB-4101 to rat cerebral cortex membranes. Rauwolscine and yohimbine had much higher affinity to the 3H-clonidine than to the 3H-WB-4101 site, whereas the reverse was true for corynanthine. The results indicate that the 3H-clonidine site is an alpha 2-adrenoceptor and not an agonist-selective site whereas the 3H-WB-4101 site is an alpha 1-andrenoceptor and not an antagonist-selective site.

Binding to alpha-adrenergic receptors: differential pharmacological potencies and binding affinities of benzodioxanes.

We have compared the influence of a series of benzodioxane alpha-adrenergic antagonists on 3H-WB-4101 and 3H-clonidine binding to alpha-receptor sites in the brain and peripheral tissues with their pharmacological properties. The drug specificity of 3H-WB-4101 binding is quite similar in central and peripheral tissues. Pharmacological potencies of benzodioxanes at postsynaptic alpha-receptors in the rat vas deferens correlate with potencies at 3H-WB-4101 but not at 3H-clonidine binding sites. These findings suggest pharmacological effects of these drugs are mediated by "alpha-1 postsynaptic receptors" labeled by 3H-WB-4101. For several benzodioxanes absolute pharmacological potencies at postsynaptic alpha-receptors of the rat vas deferens are substantially less than their potencies at 3H-WB-4101 sites. The potencies of benzodioxane analogues at 3H-clinidine binding sites are similar to their pharmacological potencies at presynaptic autoreceptors in the rat vas deferens.