Comparative structure-activity relationships of benztropine analogues at the dopamine transporter and histamine H(1) receptors.

Article Details

Citation

Copy to clipboard

Kulkarni SS, Kopajtic TA, Katz JL, Newman AH

Comparative structure-activity relationships of benztropine analogues at the dopamine transporter and histamine H(1) receptors.

Bioorg Med Chem. 2006 Jun 1;14(11):3625-34. Epub 2006 Feb 3.

PubMed ID

16460947 [ View in PubMed

]

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 (K(i)=16-37,600 nM) and DAT (K(i)=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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Benzatropine	Histamine H1 receptor	Protein	Humans	Unknown	Antagonist	Details
Benzatropine	Sodium-dependent dopamine transporter	Protein	Humans	Yes	Inhibitor	Details