Morcillo Mj

Comparative receptor mapping of serotoninergic 5-HT3 and 5-HT4 binding sites*

The clinical use of currently available drugs acting at the5-HT4 receptor has been hampered by their lack of selectivityover 5-HT3 binding sites. For this reason, there is considerableinterest in the medicinal chemistry of these serotonin receptor subtypes, andsignificant effort has been made towards the discovery of potent and selectiveligands. Computer-aided conformational analysis was used to characterizeserotoninergic 5-HT3 and 5-HT4 receptorrecognition. On the basis of the generally accepted model of the5-HT3 antagonist pharmacophore, we have performed a receptormapping of this receptor binding site, following the active analog approach(AAA) defined by Marshall. The receptor excluded volume was calculated as theunion of the van der Waals density maps of nine active ligands(pKi ≥ 8.9), superimposed in pharmacophoric conformations.Six inactive analogs (pKi < 7.0) were subsequently used todefine the essential volume, which in its turn can be used to define theregions of steric intolerance of the 5-HT3 receptor. Five activeligands (pKi ≥ 9.3) at 5-HT4 receptors wereused to construct an antagonist pharmacophore for this receptor, and todetermine its excluded volume by superimposition of pharmacophoricconformations. The volume defined by the superimposition of five inactive5-HT4 receptor analogs that possess the pharmacophoric elements(pKi ≤ 6.6) did not exceed the excluded volume calculated forthis receptor. In this case, the inactivity may be due to the lack of positiveinteraction of the amino moiety with a hypothetical hydrophobic pocket, whichwould interact with the voluminous substituents of the basic nitrogen ofactive ligands. The difference between the excluded volumes of both receptorshas confirmed that the main difference is indeed in the basic moiety. Thus,the 5-HT3 receptor can only accommodate small substituents inthe position of the nitrogen atom, whereas the 5-HT4 receptorrequires more voluminous groups. Also, the basic nitrogen is located at ca.8.0 Å from the aromatic moiety in the 5-HT4 antagonistpharmacophore, whereas this distance is ca. 7.5 Å in the5-HT3 antagonist model. The comparative mapping of bothserotoninergic receptors has allowed us to confirm the three-componentpharmacophore accepted for the 5-HT3 receptor, as well as topropose a steric model for the 5-HT4 receptor binding site. Thisstudy offers structural insights to aid the design of new selective ligands,and the resulting models have received some support from the synthesis of twonew active and selective ligands: 24 (Ki(5-HT3)= 3.7 nM; Ki(5-HT4) > 1000 nM) and 25(Ki(5-HT4) = 13.7 nM;Ki(5-HT3) > 10 000 nM).

Serotonin 5-HT7 Receptor Antagonists

The 5-HT7R is the most recent addition to the burgeoning family of serotonin receptors. Preliminary evidences suggest that it may be involved in depression, control of circadian rhythms, and relaxation in a variety of vascular smooth muscles, indicating the high potential of 5-HT7R ligands as new therapeutic drugs. During the last four years several selective 5-HT7R antagonists have been discovered, and we have recently contributed to this field with the definition of a pharmacophoric hypothesis for 5-HT7R antagonism and a computational model of ligand-receptor interaction of new naphtholactam and naphthosultam derivatives acting at this receptor. This article will review the development of 5-HT7R antagonists with an emphasis on selective antagonists, their structural requirements and ligand-receptor interactions, as well as the potential therapeutic opportunities surrounding 5-HT7R ligands.

Biochemical, Electrophysiological and Neurohormonal Studies with B-20991, a Selective 5-HT1A Receptor Agonist

Different receptor subtypes mediate the effects produced by serotonin (5-HT) in mammals. Besides their proved anxiolytic action, agonists of the 5-HT1A receptor subtype show prospects as antidepressants or neuroprotective agents in case of ischemia. In order to better define the pharmacological profile and determine the selectivity for the 5-HT receptor type, the properties of the new 5-HT1A receptor agonist 2[[4-(o-methoxyphenyl)piperazin-1-yl]-methyl]-1.3-dioxoperhydroimidazo[1.5-a]pyridine (B-20991), an arylpiperazine derivative, have now been further studied. B-20991 was found to antagonize the forskolin-induced increase of cAMP synthesis in a HeLa cell line transfected with the human 5-HT1A in a process sensitive to the selective blocker N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxamide maleate (WAY 100635). Additionally, B-20991 showed a dose-dependent inhibition of the spontaneous on-going activity of serotonin (5-HT) neurons in the dorsal raphe nucleus in rats, an effect that was reversed by treatment with WAY 100635. This, together with the fact that the hypothermia induced by B-20991 in mice was also antagonized by WAY 100635, suggests that the new compound acts upon somatodendritic 5-HT1A receptors. Additional activation of 5-HT1A postsynaptic receptors was indicated by the increase of corticosterone plasma levels induced by B-20991 in the rat. These results demonstrate that B-20991 is a selective 5-HT1A receptor agonist acting both pre- and postsynaptically, which represents an useful pharmacological tool to study 5-HT1A-receptor-mediated effects.

Synthesis, structure and cytostatic activity of a series of 2-substituted perimidines☆

Abstract The synthesis and cytotoxic activity of a series of 2-substituted perimidines is reported. The presence of a basic nitrogen in position 2 of the chain is very important for activity. The maximal activity appears in the 2-dimethylaminomethylene derivative.