創薬
選択的GPR52作動薬HTL-Aの前臨床における薬力学的および薬物動態学的特性
By Clíona MacSweeney et al. | May 7, 2020
サマリー
当社グループのアソシエイトディレクターであるClíona MacSweeneyがこのほど、Society of Biological Psychiatry（生物学的精神医学会）75周年記念会議のポータルサイトに、新規GPR52作動薬の薬力学的および薬物動態学的特性についてのポスターを掲載しました。登録メンバーはこちらのポータルサイトよりポスターとプレゼンテーションを閲覧できます。Clionaのポスターはこのページの一番下「ポスターを見る」よりご覧いただけます。
概要
Background
GPR52 has been proposed as a target for the treatment of positive, negative and cognitive symptoms of schizophrenia. High expression of the receptor on D2 receptor-expressing medium spiny neurons and D1 cortical neurons suggests that a GPR52 agonist will selectively modulate dopaminergic and glutamatergic signalling without causing the adverse effects associated with antipsychotics. The pharmacokinetic properties of HTL-A, a selective GPR52 agonist (pEC50 7.5), were measured in preclinical species and pharmacodynamic effects were explored in the rat subchronic PCP-induced cognitive deficit model. A neurobehavioural (Irwin) test was performed following repeat dosing to evaluate potential adverse nervous system effects.
Methods
Reversal learning was tested following HTL-A treatment (1-30 mg/kg, PO) in female Lister Hooded rats previously treated with PCP (2 mg/kg, IP) twice daily for 7 days. Irwin and catalepsy tests were performed in male Wistar rats during 10 days’ treatment at 10-100 mg/kg/d, PO. Further studies were performed to understand the pharmacokinetics and bioavailability in preclinical species.
Results
HTL-A reversed the subchronic PCP-induced reversal learning deficit across a range of doses (p<0.05 vs vehicle at 5-30 mg/kg) and no adverse effects were observed in the Irwin or catalepsy tests. HTL-A demonstrates excellent pharmacokinetic properties across preclinical species, with predicted low clearance and good bioavailability in human.
Conclusions
Overall, these studies support the progression of HTL-A as a safe treatment for cognitive dysfunction in patients with psychotic disorders.