Abstract
Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a potent 5-HT1AR agonist with a moderate 5-HT1AR selectivity. In an extension of this work a series of derivatives of 1, obtained by combining different heterocyclic rings with a more flexible amine chain, was synthesized and tested for binding affinity and activity at 5-HT1AR and α1 adrenoceptors. The results led to the identification of 14 and 15 as novel 5-HT1AR partial agonists, the first being outstanding for selectivity (5-HT1A/α1d = 80), the latter for potency (pD2 = 9.58) and efficacy (Emax = 74%). Theoretical studies of ADME properties shows a good profile for the entire series and MDCKII-MDR1 cells permeability data predict a good BBB permeability of compound 15, which possess a promising neuroprotective activity. Furthermore, in mouse formalin test, compound 15 shows a potent antinociceptive activity suggesting a new strategy for pain control.
Highlights
Serotonin (5-hydroxytryptamine, 5-HT) is a relevant neurotransmitter both in the central nervous system and in periphery
The results led to the identification of 14 and 15 as novel 5-HT1A receptor (5-HT1AR) partial agonists, the first being outstanding for selectivity (5-HT1A/ α1d = 80), the latter for potency and efficacy ( Emax = 74%,)
5-HT1AR agonists have shown neuroprotective properties indicating their utility for the treatment of many neurodegenerative disorders, including Parkinson's disease (PD) and ischemic stroke [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32]
Summary
Serotonin (5-hydroxytryptamine, 5-HT) is a relevant neurotransmitter both in the central nervous system and in periphery. Unlike 1, compound 8 was able to establish an additional H-bond between the 2-methoxy oxygen atom and Y195 (Figure 11) This kind of positioning could be due to the presence of a flexible linker, as observed within all the members of the series (dioxa-, oxathia- dithiaspiro-decane derivatives), being in agreement with the higher affinity values of 8, 12 and 15 with respect to 1, 10 and 13. The absence of an aromatic substituent on the spiro-cyclic moiety could cause a reversed ligand binding mode with respect to A, guiding the phenyl or methoxy-phenyl group towards Y254, F364, F365 residues In this way, a number of π-π stacking contacts were conserved, as for A, the relevant H-bond interaction with K385 is lost, resulting in lower affinity values
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