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Antipsychotic Agents: Biased Agonism at Serotonin 5-HT1A Receptors (POSTER).

McCreary A, Newman-Tancredi A.
Serotonin Club Meeting, Montpell 11 July 2012 May 10.

The selective agonists, F13714 and F15599, exhibit “biased agonism” (functional selectivity) at 5 HT1A receptors, with distinctive in vitro signaling profiles [1]. This translated to preferential in vivo activation of pre or post-synaptic 5-HT1A receptors, respectively [2]. However, it is unclear whether antipsychotics possessing 5-HT1A receptor agonism demonstrate biased agonism.
We therefore data-mined literature describing in vitro 5-HT1A receptor agonism of the marketed and exploratory antipsychotics: clozapine, ziprasidone, aripiprazole, adoprazine (SLV313), bifeprunox, SSR181507, F15063 and sarizotan. The effects of these drugs were compared on G protein activation [3], cAMP inhibition[3], ERK1/2 phosphorylation[4] and receptor internalization[5] assays.
Distinct rank orders of potency were observed, consistent with biased agonism. Clozapine: GTP > cAMP = internalization > ERK1/2. Ziprasidone: GTP > internalization > ERK > cAMP. Aripiprazole and SSR181507: internalization > GTP > ERK > cAMP. Bifeprunox: internalization > GTP = ERK > cAMP. Adoprazine and F15063: internalization > GTP > cAMP = ERK. Sarizotan: GTP = internalization > ERK > cAMP. Interestingly, varying degrees of efficacy were also seen across the different assay systems.
These data indicate that antipsychotics exhibit biased agonism at 5-HT1A receptors in vitro and suggest that they may differentially activate 5-HT1A receptor sub-populations in vivo [2]. It may be speculated that biased agonism at 5-HT1A receptors could ultimately serve to target antipsychotics to specific symptom domains of schizophrenia, such as negative symptoms or cognitive deficits.

1    Newman-Tancredi A, et al. Br J Pharmacol 156, 338-53 (2009).
2    Newman-Tancredi A,  Neuropsychiatry 1, 149-164 (2011).
3    Newman-Tancredi A, et al. Int J Neuropsychopharmacol 8, 341-56 (2005).
4    Bruins Slot LA, et al. Eur J Pharmacol 534, 63-70 (2006).
5    Heusler P, et al. Eur J Pharmacol 581, 37-46 (2008).