Ludo Edmond Josephine Kennis

Receptor binding profile of R 41 468, a novel antagonist at 5-HT2 receptors.

For a new antiserotonergic agent, R 41 468 and 13 reference compounds with alleged antiserotonergic activity, the receptor binding profile is reported, comprising Ki-values measured in ten different receptor binding models. R 41 468 appeared to be a particularly selective agent with respect to differentiation between two 5-hydroxytryptamine (5-HT) receptor models; it primarily displayed high binding affinity for 5-HT2 receptors and was inactive at 5-HT1 receptors. Besides showing a moderate binding affinity for histamine1 and α1 adrenergic receptors, the compound was very weakly active at dopamine receptors and inactive at the remaining receptors. Receptor binding profiles of the reference compounds differed widely. Apart from R 41 468 no other compound showed a similar selectivity towards 5-HT2 receptors. Reference compounds either poorly differentiated between 5-HT2 and 5-HT1 receptors, showed other primary effects, or were only moderately active. In the 5-HT2 and 5-HT1 receptor binding models the ‘D-receptor’ antagonist phenoxybenzamine was weakly active and the ‘M-receptor’ antagonist morphine was inactive. It is concluded that R 41 468 will be a particularly suitable tool to antagonize 5-HT action mediated by 5-HT2 receptors.

New 2-substituted 1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine having highly active and potent central α2-antagonistic activity as potential antidepressants

The synthesis and biological activity of a series of benzofuro[3,2-c]pyridines and a benzothieno[3,2-c]pyridine are described. These compounds exhibit high affinity for the alpha 2-adrenoceptor, with high selectivity versus the alpha 1-receptor. Compound 1 also shows potent in vivo central activity and has been selected for further biological and clinical evaluation.

5 Risperidone and related 5HT2/D2 antagonists: A new type of antipsychotic agent?

Publisher Summary This chapter describes the historical development (including syntheses) and pharmacological profile of risperidone, and investigates to what extent its basic pharmacological properties (combined 5HT 2 /D 2 antagonism) occur among experimental and available neuroleptics. The medicinal chemistry programme that ultimately led to risperidone, was initially based on the chemical structures of the neuroleptics lenperone and benperidol, and on the pharmacological differences between haloperidol and pipamperone. Apart from risperidone, the programme generated a variety of pharmacologically distinct compounds, among others the neuroleptics declenperone, milenperone, pirenperone, setoperone, and ocaperidone; the antiemetic and gastrokinetic domperidone; the antihypertensive ketanserin; and the 5HT 2 antagonists seganserin and ritanserin. In a series of benzisoxazole derivatives, risperidone was found to be different in pharmacological profile from haloperidol and comparable to pipamperone except for its higher potency for 5HT 2 and D 2 antagonism. The combined 5HT 2 /D 2 antagonism of risperidone seems to result in synergistic effects. Risperidone , but not haloperidol is more potent against the agitation elicited by a combined tryptamine-apomorphine challenge than against the agitation elicited by apomorphine alone. This synergism of combined 5HT 2 /D 2 antagonism may result in a more efficient control of interacting serotonergic and dopaminergic stimuli than with conventional neuroleptics.