ABSTRACT
Pyrazolines 7-10 were designed as novel CB(1) receptor antagonists, which exhibited improved turbidimetric aqueous solubilities. On the basis of their extended CB(1) antagonist pharmacophore, hybrid molecules exhibiting cannabinoid CB(1) receptor antagonistic as well as acetylcholinesterase (AChE) inhibiting activities were designed. The target compounds 12, 13, 20, and 21 are based on 1 (tacrine) as the AChE inhibitor (AChEI) pharmacophore and two different CB(1) antagonistic pharmacophores. The imidazole-based 20 showed high CB(1) receptor affinity (48 nM) in combination with high CB(1)/CB(2) receptor subtype selectivity (>20-fold) and elicited equipotent AChE inhibitory activity as 1. Molecular modeling studies revealed the presence of a binding pocket in the AChE enzyme which nicely accommodates the CB(1) pharmacophores of the target compounds 12, 13, 20, and 21.
Subject(s)
Acetylcholinesterase/chemistry , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/pharmacology , Drug Design , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Tacrine/analogs & derivatives , Tacrine/chemistry , Animals , CHO Cells , Cannabinoids/metabolism , Cells, Cultured , Cholinesterase Inhibitors/chemistry , Cricetinae , Cricetulus , Crystallography, X-Ray , Humans , Kidney/cytology , Kidney/drug effects , Models, Molecular , Molecular Structure , Protein Conformation , Structure-Activity Relationship , Tacrine/chemical synthesis , Tacrine/pharmacologyABSTRACT
A series of novel bicyclic 1-heteroaryl-4-[omega-(1H-indol-3-yl)alkyl]piperazines was synthesized and evaluated on binding to dopamine D(2) receptors and serotonin reuptake sites. This class of compounds proved to be potent in vitro dopamine D(2) receptor antagonists and in addition were highly active as serotonin reuptake inhibitors. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both the antagonism of apomorphine-induced climbing and the potentiation of 5-HTP-induced behavior in mice. On the basis of the preclinical data, 8-{4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazin-1-yl}-4H-benzo[1,4]oxazin-(R)-2-methyl-3-one (45c, SLV314) was selected for clinical development. In vitro and in vivo studies revealed that 45c has favorable pharmacokinetic properties and a high CNS-plasma ratio. Molecular modeling studies showed that the bifunctional activity of 45c can be explained by its ability to adopt two different conformations fitting either the dopamine D(2) receptor pharmacophore or the serotonin transporter pharmacophore.
Subject(s)
Antipsychotic Agents/chemical synthesis , Benzoxazines/chemical synthesis , Dopamine D2 Receptor Antagonists , Indoles/chemical synthesis , Piperazines/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemical synthesis , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Antipsychotic Agents/pharmacokinetics , Antipsychotic Agents/pharmacology , Benzoxazines/pharmacokinetics , Benzoxazines/pharmacology , Biological Transport , CHO Cells , Cell Line , Cricetinae , Cricetulus , Indoles/pharmacokinetics , Indoles/pharmacology , Male , Models, Molecular , Piperazines/pharmacokinetics , Piperazines/pharmacology , Rats , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Novel 3,4-diarylpyrazolines 1 as potent CB1 receptor antagonists with lipophilicity lower than that of SLV319 are described. The key change is the replacement of the arylsulfonyl group in the original series by a dialkylaminosulfonyl moiety. The absolute configuration (4S) of eutomer 24 was established by X-ray diffraction analysis and 24 showed a close molecular fit with rimonabant in a CB1 receptor-based model. Compound 17 exhibited the highest CB1 receptor affinity (Ki = 24 nM) in this series, as well as very potent CB1 antagonistic activity (pA2 = 8.8) and a high CB1/CB2 subtype selectivity (approximately 147-fold).
Subject(s)
Pyrazoles/chemical synthesis , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Cannabinoids/antagonists & inhibitors , Humans , Hydrophobic and Hydrophilic Interactions , Molecular Structure , Pyrazoles/pharmacology , Stereoisomerism , Structure-Activity Relationship , Sulfonamides , X-Ray DiffractionABSTRACT
A series of novel 3,4-diarylpyrazolines was synthesized and evaluated in cannabinoid (hCB(1) and hCB(2)) receptor assays. The 3,4-diarylpyrazolines elicited potent in vitro CB(1) antagonistic activities and in general exhibited high CB(1) vs CB(2) receptor subtype selectivities. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both a CB agonist-induced blood pressure model and a CB agonist-induced hypothermia model. Chiral separation of racemic 67, followed by crystallization and an X-ray diffraction study, elucidated the absolute configuration of the eutomer 80 (SLV319) at its C(4) position as 4S. Bioanalytical studies revealed a high CNS-plasma ratio for the development candidate 80. Molecular modeling studies showed a relatively close three-dimensional structural overlap between 80 and the known CB(1) receptor antagonist rimonabant (SR141716A). Further analysis of the X-ray diffraction data of 80 revealed the presence of an intramolecular hydrogen bond that was confirmed by computational methods. Computational models and X-ray diffraction data indicated a different intramolecular hydrogen bonding pattern in the in vivo inactive compound 6. In addition, X-ray diffraction studies of 6 revealed a tighter intermolecular packing than 80, which also may contribute to its poorer absorption in vivo. Replacement of the amidine -NH(2) moiety with a -NHCH(3) group proved to be the key change for gaining oral biovailability in this series of compounds leading to the identification of 80.
