New Serotonin 5-HT_1A Receptor Agonists with Neuroprotective Effect against Ischemic Cell Damage

Abstract

We report the synthesis of new compounds 4− 35 based on structural modifications of different moieties of previously described lead UCM-2550. The new nonpiperazine derivatives, representing second-generation agonists, were assessed for binding affinity, selectivity, and functional activity at the 5-HT 1A receptor (5-HT 1A R). Computational β 2 -based homology models of the ligand−receptor complexes were used to explain the observed structure−affinity relationships. Selected candidates were also evaluated for their potential in vitro and in vivo neuroprotective properties. Interestingly, compound 26 (2-{6-[(3,4-dihydro-2H-chromen-2-ylmethyl)amino]hexyl}tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione) has been characterized as a high-affinity and potent 5-HT 1A R agonist (K i = 5.9 nM, EC 50 = 21.8 nM) and exhibits neuroprotective effect in neurotoxicity assays in primary cell cultures from rat hippocampus and in the MCAO model of focal cerebral ischemia in rats.

Neuroprotective mechanism of the novel melatonin derivative Neu-P11 in brain ischemia related models

“…A possible interpretation for these results could lie on the fact that Neu-P11 also interacts with 5-HT1A/1D receptors (15). It has been reported that different 5HT1A agonists are able to attenuate excitotoxicity, proving neuroprotective in global and focal ischemia animal models (36). Furthermore, some 5HT1A…”

Estrogen and Serotonin: Complexity of Interactions and Implications for Epileptic Seizures and Epileptogenesis

“…These effects were blocked by WAY 100635 (5-HT 1A receptor antagonist), thereby confirming the neuroprotective properties of 5-HT 1A receptors [164]. Marco et al ., (2011) reported that a high-affinity and potent 5-HT 1A R agonist (2-{6-[(3,4-dihydro-2H-chromen-2-ylmethyl)amino]hexyl}-tetrahydro-1Hpyrrolo [1,2c]imidazole-1,3(2H)-dione) exhibits neuroprotective effect, which was validated using neurotoxicity assays in primary cell cultures from rat hippocampus and in the MCAO model of focal cerebral ischemia in rats [165]. Li et al ., (2010) recited neuroprotective effect of fluoxetine against 3,4-methylenedioxymethamphetamine (MDMA) induced reduction in serotonin transporter (SERT; a reliable marker for accessing the integrity of serotonergic neurons) in rat brain as examined with N,N-dimethyl-2-(2-amino-4-[18F]-fluorophenylthio) benzylamine (4-[18F]-ADAM; a SERT radioligand) and micro positron emission tomography (micro-PET) analysis.…”

The role of experimental and computational structural approaches in 7TM drug discovery

“…The homology models explained binding modes and subtype selectivity among these receptors for a diverse set of AR antagonists. Other very effective homology models were used to rationalize agonist activities at the serotonin 5HT 1A receptor [95] and the somatostatin receptor subtype 4 [39], the activity of nucleosides at the A1 and A3 receptors [96,97], and inverse agonism/antagonism versus partial/full agonism activities of b 2 AR ligands [98,99]. Constructed from the dopamine D3 receptor X-ray structure as a template, D3R and D2R homology models were refined by molecular dynamics to guide in the design of highly D3R-selective ligands with desired efficacies [100].…”