Biased agonism at serotonin 5-HT_1Areceptors: preferential postsynaptic activity for improved therapy of CNS disorders

Abstract

Practice pointsSerotonin or 5-hydroxytryptamine (5-HT) 1A receptors are attractive targets for pharmacotherapy of pathologies associated with dysfunctional serotonergic neurotransmission, including anxiety, depression, Parkinson's disease, pain and schizophrenia. 5-HT 1A receptors are expressed both as presynaptic autoreceptors on serotonergic cell bodies in the raphe and as postsynaptic heteroreceptors in multiple brain regions including the cortex, hippocampus, septum and hypothalamus.The signaling cascades elicited by 5-HT 1A receptor activation differ between brain regions: different G-protein subtypes, different second messengers and different neurochemical read-outs.The concept of 'biased agonism' or 'functional selectivity' asserts that agonists can preferentially direct receptor signaling to specific intracellular responses. This opens the possibility of targeting receptors in specific cellular environments or brain regions.F15599 is a selective 5-HT 1A receptor agonist that exhibits biased agonism, preferentially activating Gai versus Gao G-protein subtypes. F15599 preferentially activates ERK1/2 phosphorylation more than G-protein, receptor internalization or adenylyl cyclase inhibition.F15599 stimulates rat medial prefrontal cortex pyramidal neuron electrical activity and dopamine release (controlled by postsynaptic 5-HT 1A receptors) at low doses that do not inhibit raphe serotonergic neuron electrical activity or hippocampal 5-HT release (controlled by presynaptic 5-HT 1A receptors).F15599 preferentially stimulates c-Fos expression and ERK1/2 phosphorylation in rat prefrontal cortex, with less pronounced effects in the raphe. This preferential postsynaptic activity is not observed with other 5-HT 1A agonists.In rats F15599 exhibits potent antidepressant-like activity in the forced swim test, inhibits stress-induced ultrasonic vocalization and attenuates phencyclidine-induced cognitive impairments in reversal learning, in novel object recognition and in a hole-board test.At 'antidepressant' doses in rats, F15599 does not induce serotonin syndrome, does not disrupt attentional performance, does not impair working memory and does not inhibit prepulse inhibition of startle response.For reprint orders, please contact: reprints@futuremedicine.com

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…Thus, it is possible that the different CB 1 modulators tested so far exhibit functional selectivity for different types of G proteins, a phenomenon referred to as "biased agonism" (Huot et al, 2011b;Kenakin, 2011;Newman-Tancredi, 2011). For instance, although they are both CB 1 agonists, nabilone and the ethanolic extract of C. sativa might well display affinity for different subpopulations of CB 1 receptors within the basal ganglia, leading to a reduction of LID in one case (nabilone) but not in the other (C. sativa).…”

Functional selectivity – chance for better and safer drugs?

“…kinaza białkowa C, kinazy białkowe aktywowane mitogenami) [35]. Wyniki ostatnich badań wskazują, że możliwe jest farmakologiczne "celowanie" w subpopulacje receptorów 5-HT 1A w różnych strukturach mózgu [57]. Jest to związane z faktem, iż receptory 5-HT 1A zlokalizowane w różnych rejonach mózgu są powiązane z odmiennymi szlakami transdukcji sygnału i przez to mogą być selektywnie pobudzane przez stronniczych agonistów, którzy preferencyjnie aktywują poszczególne mechanizmy przekazywania sygnału wewnątrzkomórkowego [58][59][60][61][62].…”

“…Wydaje się więc, że selektywność funkcjonalna może być podstawą dla selektywności regionalnej. Oddziaływanie farmakologiczne na receptory 5-HT 1A w różnych rejonach mózgu może z kolei mieć kluczowe znaczenie dla badań nad zaburzeniami funkcji OUN, a także ich farmakoterapią [57].…”

“…protein kinase C, mitogen-activated protein kinases) [35]. Results of recent studies suggest that it is possible to pharmacologically "target" sub-populations of 5-HT 1A receptors in different brain structures [57]. It is related to the fact that 5-HT 1A receptors located in different areas of the brain are associated with different signal transduction pathways and thus can be selectively activated by biased agonists which preferentially activate individual intracellular signal transduction mechanisms [58][59][60][61][62].…”

“…Thus, it seems that functional selectivity can be the basis for regional selectivity. Pharmacological effects on 5-HT 1A receptors in different regions of the brain can in turn be of key importance for the studies on CNS dysfunction, as well as its pharmacotherapy [57].…”