Behavioural actions of two new 1-N substituted analogues of melatonin.

Melatonin has been mainly used for alleviating some disorders related with insomnia and circadian rhythmicity. The use of this hormone has been limited, among others, due to its short half-life and instability. This study reports some behavioural actions of two new melatonin analogues that incorporate a phenyl or a benzoyl group at the nitrogen atom of the melatonin molecule. Although diazepam was about 10 times more potent than either of the melatonin analogues, results show that in general these last display better anxiolytic, anticonvulsant and sedative actions than the original molecule.

Cross-talking between 5-HT3 and GABAA receptors in cultured myenteric neurons.

We recorded whole-cell ion currents induced by gamma-aminobutyric acid (I(GABA)) and serotonin (I(5-HT)) to investigate and characterize putative interactions between GABA(A) and 5-HT(3) receptors in myenteric neurons from the guinea pig small intestine. I(GABA) and I(5-HT) were inhibited by bicuculline and ondansetron, respectively. Currents induced by the simultaneous application of both, GABA and 5-HT (I(GABA+5-HT)) were significantly lower than the sum of I(GABA) and I(5-HT), indicating the existence of a current occlusion. Such an occlusion was observed when GABA(A) and 5-HT(3) receptors are virtually saturated. Kinetics, and pharmacological properties of I(GABA+5-HT) indicate that they are mediated by activation of both, GABA(A) and 5-HT(3) channels. GABA did not alter I(5-HT) in neurons without GABA(A) channels, in the presence of bicuculline (a GABA(A) receptor antagonist) or at the reversal potential for I(GABA). Similarly, 5-HT did not modify I(GABA) in neurons in which 5-HT(3) channels were absent, after inhibiting 5-HT(3) channels with ondansetron (a 5-HT(3) receptor antagonist) or at the reversal potential for I(5-HT). Current occlusion was observed as soon as GABA(A) and 5-HT(3) channels were being activated, in the absence of Ca(2+), at low temperature (11 degrees C), and after adding staurosporine (a protein kinase inhibitor) to the pipette solution. Our proposal is that GABA(A) and 5-HT(3) channels are organized in clusters and within these, both channels can cross-inhibit each other, likely by allosteric interactions between these proteins.

Receptor-binding studies of 1-N-substituted melatonin analogues.

In order to analyse the relevance of the indole electronic region in the binding of melatonin to its receptors, we prepared several analogues with p-H, p-NO(2), p-MeO, p-F and p-Me of benzyl, benzoyl and phenyl substituents at position 1 of the melatonin skeleton. The electronic properties of the analogues, as calculated with the semiempirical method AM1, were correlated with their affinity for the melatonin receptor from chicken brain membranes. Different trends were observed for each compound series. Compound 5c, with a p-NO(2)-benzoyl group, showed the best affinity indicating the importance of a polar bulky group in the receptor interaction.