Bifeprunox: A Novel Antipsychotic Agent with Partial Agonist Properties at Dopamine D2 and Serotonin 5-HT _1A Receptors

Abstract

Most second-generation, atypical, dopamine (DA) D2/5-HT2 blocking antipsychotics still induce extrapyramidal side effects (EPS) in higher doses. Weight gain and metabolic disturbances are also a problem, and negative and cognitive symptoms have not been sufficiently addressed. The current brain DA mesolimbic hyperactive/mesocortical hypoactive hypothesis of schizophrenia suggests that DA D2/5-HT 1A receptor partial agonist properties may be more efficacious with less side effects. DA D2 receptor partial agonists may stabilize a hyperactive/hypoactive DA condition. Additional 5-HT 1A stimulation may enhance therapeutic efficacy and also improve EPS liability profile. In clinical trials in schizophrenic patients, the novel DA D2/5-HT 1A partial agonist bifeprunox indeed demonstrates therapeutic efficacy, a safe EPS profile and appears beneficial regarding weight gain, prolactin, blood lipid and glucose levels and cardiac rhythm. The data on bifeprunox are promising and suggest that combined DA D2/5-HT 1A partial agonism may well be important properties for future-generation antipsychotics.Bifeprunox, a novel antipsychotic agent with a so-called third-generation atypical pharmacological profile, is currently in clinical trials and expected to launch as a schizophrenia therapy in the American market sometime in 2007, and in Europe in 2008. It is also being considered for treatment of bipolar disorder [101]. BackgroundSchizophrenia affects around 1% of the general population worldwide. The symptomatology includes positive symptoms (e.g., hallucinations, delusions and paranoia), negative symptoms (e.g., social withdrawal, poverty of speech, flat affect), as well as features of cognitive impairment. The main pharmacological property and therapeutic mechanism of action of traditional antipsychotic drugs (APDs), such as haloperidol (Haldol ® ), is dopamine (DA) D2 receptor blockade. However, owing to high DA D2 receptor occupancy in therapeutic doses, treatment with these drugs is frequently accompanied by disturbing extrapyramidal side effects (EPS), such as acute dystonia and parkinsonism, as well as endocrine effects such as increased prolactin levels. While effective against positive symptoms, these drugs have, over time, proven to be less efficacious against negative symptoms and cognitive impairment, and may even worsen these symptoms.The antipsychotic clozapine (Leponex ® , Clozaril ® ), a dibenzodiazepine that was introduced in 1967 [1], on the other hand, is pharmacologically different, with a multireceptor affinity profile (DA D1, D2, D4, 5-HT 2A /C, 5-HT 1A , histamine H1, α 1 , α 2 , cholinergic muscarinic receptor affinity) and comparatively lower affinity for the DA D2 receptor than traditional APDs. Clozapine produces good antipsychotic effect with virtually no EPS in therapeutic doses, and was therefore labeled atypical. Compared with traditional APDs, clozapine also shows superior therapeutic efficacy in treatment-resistant patients [2,3], beneficial effects against some aspects of cognitive impairment [...

Aripiprazole Increases the PKA Signalling and Expression of the GABAA Receptor and CREB1 in the Nucleus Accumbens of Rats

“…A 0.75 mg/kg aripiprazole dosage in rats is equivalent to ~7.5 mg in humans (60 kg body weight), while 0.8 mg/kg bifeprunox and 0.1 mg/kg haloperidol is equivalent to ~8 mg and ~1 mg respectively, all of which are within the used/recommended clinical dosages (Casey et al, 2008, Emsley, 2009, Mace and Taylor, 2009. It was reported that aripiprazole and bifeprunox, at these dosages, had over 90% D 2 receptor occupancy in rat brains (Wadenberg, 2007), while haloperidol reached approximately 70% D 2 R occupancy , Naiker et al, 2006, Natesan et al, 2006. Furthermore, the dosages used in this study have been shown to be physiologically and behaviourally effective in rodents (Assie et al, 2006, De Santis et al, 2014, Han et al, 2009, Kesby et al, 2006, Wadenberg, 2007, whilst not causing EPS side-effects (Natesan et al, 2006, Wadenberg, 2007.…”

“…It was reported that aripiprazole and bifeprunox, at these dosages, had over 90% D 2 receptor occupancy in rat brains (Wadenberg, 2007), while haloperidol reached approximately 70% D 2 R occupancy , Naiker et al, 2006, Natesan et al, 2006. Furthermore, the dosages used in this study have been shown to be physiologically and behaviourally effective in rodents (Assie et al, 2006, De Santis et al, 2014, Han et al, 2009, Kesby et al, 2006, Wadenberg, 2007, whilst not causing EPS side-effects (Natesan et al, 2006, Wadenberg, 2007. After 1-week administration, all rats were sacrificed between 10:00 AM and 12:00 PM to minimise possible circadian-induced variation of protein expression.…”

New Arylpiperazinylalkyl Derivatives of 8‐Alkoxy‐purine‐2,6‐dione and Dihydro[1,3]oxazolo[2,3‐f]purinedione Targeting the Serotonin 5‐HT1A/5‐HT2A/5‐HT7 and Dopamine D2 Receptors

“…Since the introduction of aripiprazole in 2002 and then paliperidone, iloperidone, asenapine, and lurasidone, there has been a relative hiatus in the development of new atypical antipsychotic drugs. From the chemical point of view, the new antidepressants and atypical antipsychotics are based around arylpiperazine or arylpiperidine core structures, which may explain their interaction with a large number of G-protein coupled receptors (Rs), including 5-HT 1A , 5-HT 2A , 5-HT 6 , 5-HT 7 as well as D 2 , D 3 , and D 4 receptors. Clues from the clinic that atypical antipsychotics agents can be used as augmentation therapy in patients with poor responses to antidepressants led to the creation of the multitarget strategy for development of CNS active drugs.…”

“…1), a potential atypical antipsychotic with reduced extrapyramidal side effects [6]. The structure-activity relationships in the group of 1-aryl-4-(phenylarylmethyl)piperazines [7] led to obtaining SLV 313 (adoprazine) (Fig.…”

“…For several years, we have been interested in developing LCAPs derivatives of 1,3-dimethyl-purine-2,6-dione, which were mainly evaluated toward 5-HT 1A , 5-HT 2A , 5-HT 7 , and recently also for 5-HT 6 Rs [12][13][14][15][16][17][18][19][20]. The 8-unsubstituted or 8-alkoxy-and 8-morpholinyl-purine-2,6-dione derivatives showed the features of dual 5HT 1A /5HT 2A or 5-HT 1A /5HT 7 Rs ligands with a moderate affinity toward D 2 sites.…”