AbstractThe aim of this study was to use a combined structure and pharmacophore modeling approach to extract information regarding dopamine D1 receptor agonism and D1/D2 agonist selectivity. A 3D structure model of the D1 receptor in its agonist‐bound state was constructed with a full D1 agonist present in the binding site. Two different binding modes were identified using (+)‐doxanthrine or SKF89626 in the modeling procedure. The 3D model was further compared with a selective D1 agonist pharmacophore model. The pharmacophore feature arrangement was found to be in good agreement with the binding site composition of the receptor model, but the excluded volumes did not fully reflect the shape of the agonist binding pocket. A new receptor‐based pharmacophore model was developed with forbidden volumes centered on atom positions of amino acids in the binding site. The new pharmacophore model showed a similar ability to discriminate as the previous model. A comparison of the 3D structures and pharmacophore models of D1 and D2 receptors revealed differences in shape and ligand‐interacting features that determine selectivity of D1 and D2 receptor agonists. A hydrogen bond pharmacophoric feature (Ser‐TM5) was shown to contribute most to the selectivity. Non‐conserved residues in the binding pocket that strongly contribute to D1/D2 receptor agonist selectivity were also identified; those were Ser/Cys3.36, Tyr/Phe5.38, Ser/Tyr5.41, and Asn/His6.55 in the transmembrane (TM) helix region, together with Ser/Ile and Leu/Asn in the second extracellular loop (EC2). This work provides useful information for the design of new selective D1 and D2 agonists. The combined receptor structure and pharmacophore modeling approach is considered to be general, and could therefore be applied to other ligand–protein interactions for which experimental information is limited.

01 Jan 1996·Journal of Medicinal ChemistryQ1 · MEDICINE

Conformational Analysis of D₁ Dopamine Receptor Agonists: Pharmacophore Assessment and Receptor Mapping

Q1 · MEDICINE

Article

Author: Nichols, David E. ; Mottola, David M. ; Mailman, Richard B. ; Laiter, Sergei ; Watts, Val J. ; Tropsha, Alexander ; Wyrick, Steven D.

Compute-aided conformational analysis was used to characterize the agonist pharmacophore for D1 dopamine receptor recognition and activation. Dihydrexidine (DHX), a high-affinity full agonist with limited conformational flexibility, served as a structural template that aided in determining a molecular geometry that would be common for other more flexible, biologically active agonists. The intrinsic activity of the drugs at D1 receptors was assessed by their ability to stimulate adenylate cyclase activity in rat striatal homogenates (the accepted measure of D1 receptor activation). In addition, affinity data on 12 agonists including six purported full agonists (dopamine, dihydrexidine, SKF89626, SKF82958, A70108, and A77636), as well as six less efficacious structural analogs, were obtained from D1 dopamine radioreceptor-binding assays. The active analog approach to pharmacophore building was applied as implemented in the SYBYL software package. Conformational analysis and molecular mechanics calculations were used to determine the lowest energy conformation of the active analogs (i.e., full agonists), as well as the conformations of each compound that displayed a common pharmacophoric geometry. It is hypothesized that DHX and other full agonists may share a D1 pharmacophore made up of two hydroxy groups, the nitrogen atom (ca. 7 A from the oxygen of m-hydroxyl) and the accessory ring system characterized by the angle between its plane and that of the catechol ring (except for dopamine and A77636). For all full agonists (DHX, SKF89626, SKF82958, A70108, A77636, and dopamine), the energy difference between the lowest energy conformer and those that displayed a common pharmacophore geometry was relatively small (< 5 kcal/mol). The pharmacophoric conformations of the full agonists were also used to infer the shape of the receptor binding site. Based on the union of the van der Waals density maps of the active analogs, the excluded receptor volume was calculated. Various inactive analogs (partial agonists with D1 K0.5 > 300 nM) subsequently were used to define the receptor essential volume (i.e., sterically intolerable receptor regions). These volumes, together with the pharmacophore results, were integrated into a three-dimensional model estimating the D1 receptor active site topography.

01 Jan 1989·European Journal of PharmacologyQ3 · MEDICINE

Amphetamine discrimination: effects of dopamine receptor agonists

Q3 · MEDICINE

Article

Author: Erik B. Nielsen ; Peter H. Andersen ; Kirsten Randrup

Dopamine (DA) D-1 and D-2 receptor agonists and antagonists were characterized in receptor binding and adenylate cyclase assays with respect to affinity, selectivity and efficacy. The ability of the ligands to interact with the discriminative stimulus effects of d-amphetamine (AMPH) was then assessed. The D-2 agonists, quinpirole, pergolide and CH 29-717, substituted completely for AMPH while neither partial (SKF 38393 and SKF 75670) nor full D-1 receptor agonists (SKF 89626 and SKF 81297) substituted. On the other hand, the selective D-1 and D-2 antagonists all blocked AMPH. The substitution for AMPH by pergolide was blocked by raclopride but not by SCH 23390, indicating D-2 mediation. In contrast, the motor effects of pergolide were blocked by both raclopride and SCH 23390, indicating mixed D-1/D-2 receptor involvement. These results suggest that D-1 and D-2 are equally involved in the expression of functional effects in the DAergic motor systems. Conversely, D-2 receptors may play a primary role in the DA systems involved in the AMPH cue; furthermore, the D-1 and D-2 receptors in the systems are relatively uncoupled.

100 Deals associated with SKF-89626

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Nervous System Diseases	Discovery	GB	Smithkline Beecham Plc	-
Nervous System Diseases	Discovery	DE	Bayer Schering Pharma AG	-

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

SKF-89626

Overview

Basic Info

Structure

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation