No abstract

We investigated the structural requirements for high 5-HT1A affinity of the agonist flesinoxan and its selectivity versus D2 receptors. For this purpose a series of arylpiperazine congeners of flesinoxan were synthesized and evaluated for their ability to displace [3H]-8-OH-DPAT and [3H]spiperone from their specific binding sites in rat frontal cortex homogenates and rat striatum, respectively. Variations were made in the N4-substituent and the arylpiperazine region. Effects of N4-substitution in the investigated compounds appeared to be quite similar for 5-HT1A- and D2-receptor affinity. Lipophilicity at a distance of four carbon atoms from the piperazine N4 atom seems to be the main contributing factor to affinity for both receptors. Our data show that the amide group in the flesinoxan N4-substituent is unlikely to interact with the 5-HT1A receptor but, instead, acts as a spacer. In contrast to the structure-affinity relationships (SARs) of the N4-substituents, selectivity for 5-HT1A versus D2 receptors was gained by the arylpiperazine substitution pattern of flesinoxan. Restriction of flexibility of the N4-(benzoylamino)ethyl substituent and its effect on 5-HT1A-receptor affinity and activity were also studied. Our data show that in the bioactive conformation, the N4-[(p-fluorobenzoyl)amino]ethyl substituent is probably directed anti-periplanar relative to the HN4 atom. These results were used to dock flesinoxan (1) and two of its congeners (27 and 33) into a model of the 5-HT1A receptor that we previously reported. Amino acid residues surrounding the N4-[(p-fluorobenzoyl)amino]ethyl substituent of flesinoxan and its congeners are also present in D2 receptors. In contrast, several residues that contact the benzodioxane moiety differ from those in D2 receptors. These observations from the 3D model agree with the 5-HT1A SAR data and probably account for the selectivity of flesinoxan versus D2 receptors.

A series of novel bicyclic 1-heteroaryl-4-[omega-(1H-indol-3-yl)alkyl]piperazines was synthesized and evaluated on binding to dopamine D(2) receptors and serotonin reuptake sites. This class of compounds proved to be potent in vitro dopamine D(2) receptor antagonists and in addition were highly active as serotonin reuptake inhibitors. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both the antagonism of apomorphine-induced climbing and the potentiation of 5-HTP-induced behavior in mice. On the basis of the preclinical data, 8-{4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazin-1-yl}-4H-benzo[1,4]oxazin-(R)-2-methyl-3-one (45c, SLV314) was selected for clinical development. In vitro and in vivo studies revealed that 45c has favorable pharmacokinetic properties and a high CNS-plasma ratio. Molecular modeling studies showed that the bifunctional activity of 45c can be explained by its ability to adopt two different conformations fitting either the dopamine D(2) receptor pharmacophore or the serotonin transporter pharmacophore.

A series of 2-phenylpyrrole Mannich bases was synthesized and screened in pharmacological models for antipsychotic activity and extrapyramidal effects. Structure modifications of 5-(4-fluorophenyl)-2-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]pyrrole (1), the prototype of a new class of sodium-independent atypical dopamine D-2 antagonists, resulted in 2-[[4-(7-benzofuranyl)-1-piperazinyl]methyl]-5-(4-fluorophenyl)pyrrole (15), which was an even more potent and selective D-2 antagonist than the parent compound. The excellent oral activity in the apomorphine-induced climbing behavior and the conditioned avoidance response tests and the absence of catalepsy make this compound particularly promising as a potential antipsychotic with a low propensity to induce acute extrapyramidal side effects.