The outlook for the development of serotonergic drugs as therapeutic medications for psychiatric disorders

TY - CHAP

T1 - The outlook for the development of serotonergic drugs as therapeutic medications for psychiatric disorders

AU - Tricklebank, Mark D.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The discovery of a large number of subtypes of 5-HT receptor led to intense efforts to synthesize compounds with high affinity and selectivity for each subtype. However, the rush to be first ignored the need for detailed scientific investigation in order to allow a logical choice of target for the disease in question. Consequently subtype selective compounds proceeded into development often with little knowledge of appropriate dose or clinical indication. The clinical benefit achieved with SSRIs biased belief that compounds would be most successful if they produced prolonged and sustained receptor stimulation. However, the opportunity to record serotonin release directly from human brain over millisecond timeframes using cyclic voltammetry demonstrated the behavioral importance of transient millisecond pulses of serotonin release. We are unlikely to be able to thoroughly investigate this technology in human subjects but cyclic voltammetry in rodent species can be done while the animals are performing quite complex translational behavioral paradigms. Such an approach might well rewrite the rule book for the identification of novel serotonergic drugs. Perhaps most disappointing has been the failure of selective 5-HT3 receptor antagonists to fulfil their preclinical promise of being novel antipsychotic anxiolytic and procognitive agents while they have positively impacted cancer chemotherapy by reducing the emetic misery caused by cytotoxic anticancer drugs. Much more promising are ligands for the 5-HT7 receptor such as the antagonist SB269970 which was found able to reverse the cognitive deficit in the rat induced by the NMDA receptor antagonist MK-801 using the translational operant delayed match to position assay of working memory concomitantly reducing the MK-801-induced increase in glutamate release in the prefrontal cortex. Somewhat overlooked has been the potential of 5-HT1B. Receptor agonist zolmitriptan to reduce alcohol primed aggression in rodents and man. While activation of 5-HT1A receptors is able to stimulate the release of oxytocin which has high therapeutic potential for the treatment of impairments in social cognition associated with schizophrenia and autism. There is surely little justification for Pharma to withdraw as they have done from psychiatric drug discovery.

AB - The discovery of a large number of subtypes of 5-HT receptor led to intense efforts to synthesize compounds with high affinity and selectivity for each subtype. However, the rush to be first ignored the need for detailed scientific investigation in order to allow a logical choice of target for the disease in question. Consequently subtype selective compounds proceeded into development often with little knowledge of appropriate dose or clinical indication. The clinical benefit achieved with SSRIs biased belief that compounds would be most successful if they produced prolonged and sustained receptor stimulation. However, the opportunity to record serotonin release directly from human brain over millisecond timeframes using cyclic voltammetry demonstrated the behavioral importance of transient millisecond pulses of serotonin release. We are unlikely to be able to thoroughly investigate this technology in human subjects but cyclic voltammetry in rodent species can be done while the animals are performing quite complex translational behavioral paradigms. Such an approach might well rewrite the rule book for the identification of novel serotonergic drugs. Perhaps most disappointing has been the failure of selective 5-HT3 receptor antagonists to fulfil their preclinical promise of being novel antipsychotic anxiolytic and procognitive agents while they have positively impacted cancer chemotherapy by reducing the emetic misery caused by cytotoxic anticancer drugs. Much more promising are ligands for the 5-HT7 receptor such as the antagonist SB269970 which was found able to reverse the cognitive deficit in the rat induced by the NMDA receptor antagonist MK-801 using the translational operant delayed match to position assay of working memory concomitantly reducing the MK-801-induced increase in glutamate release in the prefrontal cortex. Somewhat overlooked has been the potential of 5-HT1B. Receptor agonist zolmitriptan to reduce alcohol primed aggression in rodents and man. While activation of 5-HT1A receptors is able to stimulate the release of oxytocin which has high therapeutic potential for the treatment of impairments in social cognition associated with schizophrenia and autism. There is surely little justification for Pharma to withdraw as they have done from psychiatric drug discovery.

KW - Phasic transmitter release

KW - Serotonin receptor subtypes as drug targets

KW - Translational behavioral tests

UR - http://www.scopus.com/inward/record.url?scp=85081920918&partnerID=8YFLogxK

U2 - 10.1016/B978-0-12-813323-1.00003-7

DO - 10.1016/B978-0-12-813323-1.00003-7

M3 - Chapter

SN - 9780128133248

SP - 269

EP - 273

BT - The Serotonin System

PB - Elsevier

ER -