660844-86-0Relevant academic research and scientific papers
Molecular hybridization of 4-azahexacyclo[5.4.1.02,6.0 3,10.05,9.08,11]dodecane-3-ol with sigma (σ) receptor ligands modulates off-target activity and subtype selectivity
Banister, Samuel D.,Moussa, Iman A.,Jorgensen, William T.,Chua, Sook Wern,Kassiou, Michael
, p. 3622 - 3626 (2011/08/06)
A series of N-substituted 4-azahexacyclo[5.4.1.02,6.0 3,10.05,9.08,11]dodecan-3-ols incorporating the respective arylalkyl subunits from several known sigma (σ) receptor ligands were synthesized and evaluated for their affinity against σ receptors and dopamine receptors. The hybrid trishomocubane-derived ligands (4-6) showed good selectivity for σ1 and σ2 receptors over multiple dopamine receptors. The molecular hybrid obtained from haloperidol and 4-azahexacyclo[5.4.1.02,6.03,10.0 5,9.08,11]dodecan-3-ol (4, σ1 K i = 27 nM, σ2 Ki = 55 nM) showed reduced affinity for D1-D5 dopamine receptors when compared to haloperidol itself. The compound with the greatest σ1 affinity in the series, benzamide 4 (σ1 Ki = 7.6 nM, σ2 Ki = 225 nM) showed a complete reversal of the subtype selectivity displayed by the highly σ2 selective parent benzamide, RHM-2 (3, σ1 Ki = 10412 nM, σ2 Ki = 13.3 nM).
Design, Synthesis, and Evaluation of Metabolism-Based Analogues of Haloperidol Incapable of Forming MPP+-like Species
Lyles-Eggleston,Altundas,Xia,Sikazwe,Fan,Yang,Li,Zhang,Zhu,Schmidt,Vanase-Frawley,Shrihkande,Villalobos,Borne,Ablordeppey
, p. 497 - 508 (2007/10/03)
The long-term, irreversible, Parkinsonism-like side effects of haloperidol have been speculated to involve several mechanisms. More recently, it has been speculated that the metabolic transformation to MPP+-like species may contribute to the Parkinsonism-like side effects. Because BCPP+ and its reduced analogue have been shown to possess the potential to destroy dopamine receptors in the nigrostriatum, we have designed new analogues of haloperidol lacking the structural features necessary to form neurotoxic quaternary species but retaining their dopamine-binding capacity. The most potent agent at the D2 receptor, the homopiperidine analogue 11, was found to be equipotent to haloperidol. It was also of interest to identify analogues with DA binding profiles similar to that of clozapine at the dopamine receptor subtypes. Evaluation of the proposed agents shows that the ratio of D2 to D4 (2) binding of clozapine was mimicked by 7 [Ki(D2) = 33, Ki(D3) = 200, Ki(D4) = 11 nM; Ki(D2)/Ki(D4) = 3] and 9 [Ki(D2) = 44, Ki(D3) = 170, Ki(D4) = 24 nM; Ki(D2)/Ki(D4) = 2]. A preliminary in-vivo testing of compound 7 shows that its behavioral profile is similar to that of clozapine. This profile suggests that there is a need for further evaluation of these two synthetic agents and their enantiomers for efficacy and lack of catalepsy in animal models.
