Molecular properties affecting fast dissociation from the D2 receptor

Pharmacology of JNJ-37822681, a Specific and Fast-Dissociating D2 Antagonist for the Treatment of Schizophrenia

“…3 H]spiperone (data not shown), which is the time point used in our dissociation screening assay (Tresadern et al, 2011 …”

“…Therefore, we began screening compounds based on a fast rate of dissociation from D 2 receptors. Results of this screening campaign and the methodology used to evaluate the speed of dissociation in a screening mode have recently been published (Tresadern et al, 2011). An additional goal was to combine fast-dissociating properties with specificity for D 2 receptors to avoid the AEs related to the multiple receptor interactions of current atypical antipsychotics.…”

Clozapine, a Fast-Off-D2 Antipsychotic

“…In fact, Tresadern et al 41 have analyzed the physicochemical properties, including MW, lipophilicity, charge (pK a ), and surface area, of 1800 D2 antagonists in order to determine which properties determine the rate of dissociation from the D2 receptor. They concluded that increased hydrophilicity, increased number of nitrogen atoms, lower MW, fewer rings, less chiral centers, and increased partial positive charge all contribute to a faster dissociation from the D2 receptor.…”

“…Following the work of Tresadern et al 41 and using the radioligand dissociation method 37 in a search for a fast-off-D2 antagonist, Langlois et al 4 43 The compound has a low affinity for 5HT2A receptors (K i = 2896 nM) and for histamine H1 receptors (K i = 4931 nM). In accordance with these K i values, the compound was found to be effective in treating schizophrenia without parkinsonian motor side effects, elevated prolactin, or weight gain.…”

Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X7 receptor antagonists

“…Slowly dissociating antagonist compounds give a higher receptor occupancy due to their increased residence time, so the wash step which effectively removes any unbound ligand will favour slowly dissociating compounds. [24][25][26] Despite the higher potency of the quinoline 27, the lower calculated logP of the 3-pyridyl derivative 35 yielded a compound with a higher LiPE value than the quinoline, suggesting that it was likely to be a better 'drug-like' candidate based on its calculated physicochemical properties. Furthermore, the calculated pharmacokinetic properties of 35 were predominantly within the recommended values as suggested by Schrödinger, and with similar values to 95% of known drugs ( Table 4).…”