Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 30, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2020.115943
Keywords
Dopamine receptors; Serotonin receptors; Pyridinyl piperazine; D-2 subtype receptors; 5-HT subtype receptors; SYA16263; Apomorphine-induced climbing behavior
Funding
- NIH/NIGMS SCORE [2SC1GM116724]
- Title III Grant
- Pharmaceutical Research Center NIH/NCRR [1C06-RR12512-01]
- National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2013-00017-C]
- Anxiolytech
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This study aims to investigate the relationship between antipsychotic drugs and their binding affinities at dopamine and serotonin receptor subtypes to potentially develop new drugs with enhanced efficacy. By synthesizing structurally modified compounds, a new analog with moderate binding affinity was identified and demonstrated antipsychotic-like activity in preliminary tests.
Dopamine (DA) and serotonin (5-HT) receptors are prime targets for the development of antipsychotics. The specific role of each receptor subtype to the pharmacological effects of antipsychotic drugs remains unclear. Understanding the relationship between antipsychotic drugs and their binding affinities at DA and 5-HT receptor subtypes is very important for antipsychotic drug discovery and could lead to new drugs with enhanced efficacies. We have previously disclosed SYA16263 (5) as an interesting compound with moderate radioligand binding affinity at the D-2 & D-3 receptors (Ki = 124 nM & 86 nM respectively) and high binding affinities towards D-4 and 5-HT1A receptors (Ki = 3.5 nM & 1.1 nM respectively). Furthermore, we have demonstrated SYA16263 (5) is functionally selective and produces antipsychotic-like behavior but without inducing catalepsy in rats. Based on its pharmacological profile, we selected SYA16263 (5) to study its structure-affinity relationship with a view to obtaining new analogs that display receptor subtype selectivity. In this study, we present the synthesis of structurally modified SYA16263 (5) analogs and their receptor binding affinities at the DA and 5-HT receptor subtypes associated with antipsychotic action. Furthermore, we have identified compound 21 with no significant binding affinity at the D-2 receptor subtype but with moderate binding affinity at the D-3 and D-4 receptors subtypes. However, because 21 is able to demonstrate antipsychotic-like activity in a preliminary test, using the reversal of apomorphine-induced climbing behavior experiment in mice with SYA16263 and haloperidol as positive controls, we question the essential need of the D-2 receptor subtype in reversing apomorphine-induced climbing behavior.
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