Comparative structure–activity relationships of benztropine analogues at the dopamine transporter and histamine H1 receptors

Abstract

Benztropine (BZT) and its analogues inhibit dopamine uptake and bind with moderate to high affinity to the dopamine transporter (DAT). However, many of these compounds, in contrast to other monoamine uptake inhibitors, lack cocaine-like behavioral effects and fail to potentiate the effects of cocaine. The BZT analogues also exhibit varied binding affinities for muscarinic M 1 and histamine H 1 receptors. In this study a comparative analysis was conducted of pharmacophoric features with respect to the activities of BZT analogues at the DAT and at the histamine H 1 receptor. The BZT analogues showed a wide range of histamine H 1 receptor (Ki =16-37600 nM) and DAT (Ki=8.5-6370 nM) binding affinities. A stereoselective histamine H 1 -antagonist pharmacophore, using a five-point superimposition of classical antagonists on the template, cyproheptadine, was developed. A series of superimpositions and comparisons were performed with various analogues of BZT. In general, smaller substituents were well tolerated on the aromatic rings of the diphenyl methoxy group for both the DAT and H 1 receptor, however for the H 1 receptor, substitution at only one of the aromatic rings was preferred. The substituents at the 2-and N-positions of the tropane ring were preferred for DAT however these groups seem to overlap receptor essential regions in the histamine H 1 receptor. Molecular models at the DAT and the histamine H 1 receptor provide further insight into the structural requirements for binding affinity and selectivity that can be implemented in future drug design.

Anticonvulsant efficacy of antihistamine cyproheptadine in rats exposed to the chemical warfare nerve agent soman

“…The greatest effect of cyproheptadine on soman-induced seizures is likely due to its anticholinergic properties. Anticholinergic properties are well-studied and therapeutically used properties of first generation antihistamines (Niemegeers et al, 1982, Graudins et al, 1998, Kulkarni et al, 2006. A previous study compared anticholinergic properties of 10 different antihistamines and found that cyproheptadine had the most potent anticholinergic properties (Kubo et al, 1987, Orzechowski et al, 2005.…”

Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction

“…Subsequent studies have failed to correlate muscarinic receptor binding with the benztropines' lack of cocaine-like effects [73,74]. It should also be noted that several of these analogues demonstrated high to moderate affinity for histamine H1 receptors [75,76]. However, a relationship between H1 binding profiles and their behavioral actions was not demonstrated [76].…”

Benztropine pretreatment does not affect responses to acute cocaine administration in human volunteers

“…In humans, benztropine's effects are similar to those of the prototypic anticholinergic, atropine, while exhibiting histamine H1 antagonism similar to pyrilamine maleate (Esplin, 1970;Physicians Desk Reference, 2005). Recently, benztropine and related tropane analogs have been evaluated in preclinical studies for their inhibitory effects on the DAT (Dar et al, 2005;Desai et al, 2005a;Kulkarni et al, 2004Kulkarni et al, , 2006Reith et al, 2001;Ukario et al, 2005). Kulkarni et al's (2004) study showed that N-substituted analogs inhibited dopamine uptake and that this function was positively correlated with DAT binding affinities.…”