A bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site.

Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity and improve current medications by reducing off-target side effects. However, the lack of structural information on their binding mode impedes rational design.

Linkers in Bitopic Agonists Shape Bias Profile among Transducers for the Dopamine D2 and D3 Receptors.

Bitopic ligands bind both orthosteric and allosteric or secondary binding sites within the same receptor, often resulting in an improvement of receptor selectivity, potency, and efficacy. In particular, for both agonists and antagonists of the dopamine D2 and D3 receptors (D2R and D3R), the primary therapeutic targets for several neurological and neuropsychiatric disorders, bitopic ligand design has proved advantageous in achieving better pharmacological profiles . Although the two pharmacophores within a bitopic ligand are typically considered the main drivers of conformational change for a receptor, the role of the linker that connects the two has not yet been systematically studied for its relevance in receptor activity profiles.

Involvement of dopamine D3 receptor in impulsive choice decision-making in male rats.

Impulsive decision-making has been linked to impulse control disorders and substance use disorders. However, the neural mechanisms underlying impulsive choice are not fully understood. While previous PET imaging and autoradiography studies have shown involvement of dopamine and D2/3 receptors in impulsive behavior, the roles of distinct D1, D2, and D3 receptors in impulsive decision-making remain unclear.

Structure of the dopamine D3 receptor bound to a bitopic agonist reveals a new specificity site in an expanded allosteric pocket.

Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity, driven by the binding of the secondary pharmacophore to non-conserved regions of the receptor. Although bitopic ligands have great potential to improve current medications by reducing off-target side effects, the lack of structural information on their binding mode impedes rational design.

Chiral Cyclic Aliphatic Linkers as Building Blocks for Selective Dopamine D or D Receptor Agonists.

Linkers are emerging as a key component in regulating the pharmacology of bitopic ligands directed toward G-protein coupled receptors (GPCRs). In this study, the role of regio- and stereochemistry in cyclic aliphatic linkers tethering well-characterized primary and secondary pharmacophores targeting dopamine D and D receptor subtypes (DR and DR, respectively) is described. We introduce several potent and selective DR (; DR = 4.

Structure Activity Relationships for a Series of Eticlopride-Based Dopamine D/D Receptor Bitopic Ligands.

The crystal structure of the dopamine D receptor (DR) in complex with eticlopride inspired the design of bitopic ligands that explored (1) -alkylation of the eticlopride's pyrrolidine ring, (2) shifting of the position of the pyrrolidine nitrogen, (3) expansion of the pyrrolidine ring system, and (4) incorporation of -alkylations at the 4-position. Structure activity relationships (SAR) revealed that moving the - or expanding the pyrrolidine ring was detrimental to DR/DR binding affinities. Small pyrrolidine -alkyl groups were poorly tolerated, but the addition of a linker and secondary pharmacophore (SP) improved affinities.

Novel Dual-Target μ-Opioid Receptor and Dopamine D Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management.

The need for safer pain-management therapies with decreased abuse liability inspired a novel drug design that retains μ-opioid receptor (MOR)-mediated analgesia, while minimizing addictive liability. We recently demonstrated that targeting the dopamine D receptor (DR) with highly selective antagonists/partial agonists can reduce opioid self-administration and reinstatement to drug seeking in rodent models without diminishing antinociceptive effects. The identification of the DR as a target for the treatment of opioid use disorders prompted the idea of generating a class of ligands presenting bitopic or bivalent structures, allowing the dual-target binding of the MOR and DR.

Chirality of Novel Bitopic Agonists Determines Unique Pharmacology at the Dopamine D3 Receptor.

The dopamine D2/D3 receptor (DR/DR) agonists are used as therapeutics for Parkinson's disease (PD) and other motor disorders. Selective targeting of DR over DR is attractive because of DR's restricted tissue distribution with potentially fewer side-effects and its putative neuroprotective effect. However, the high sequence homology between the DR and DR poses a challenge in the development of DR selective agonists.

Exception That Proves the Rule: Investigation of Privileged Stereochemistry in Designing Dopamine DR Bitopic Agonists.

In this study, starting from our selective DR agonist (), we investigated the chemical space around the linker portion of the molecule via insertion of a hydroxyl substituent and ring-expansion of the -cyclopropyl moiety into a -cyclohexyl scaffold. Moreover, to further elucidate the importance of the primary pharmacophore stereochemistry in the design of bitopic ligands, we investigated the chiral requirements of ( ) by synthesizing and resolving bitopic analogues in all the and combinations of its 9-methoxy-3,4,4a,10b-tetrahydro-2,5-chromeno[4,3-][1,4] oxazine scaffold. Despite the lack of success in obtaining new analogues with improved biological profiles, in comparison to our current leads, a "negative" result due to a poor or simply not improved biological profile is fundamental toward better understanding chemical space and optimal stereochemistry for target recognition.

2016 Philip S. Portoghese Medicinal Chemistry Lectureship: Designing Bivalent or Bitopic Molecules for G-Protein Coupled Receptors. The Whole Is Greater Than the Sum of Its Parts.

The genesis of designing bivalent or bitopic molecules that engender unique pharmacological properties began with Portoghese's work directed toward opioid receptors, in the early 1980s. This strategy has evolved as an attractive way to engineer highly selective compounds for targeted G-protein coupled receptors (GPCRs) with optimized efficacies and/or signaling bias. The emergence of X-ray crystal structures of many GPCRs and the identification of both orthosteric and allosteric binding sites have provided further guidance to ligand drug design that includes a primary pharmacophore (PP), a secondary pharmacophore (SP), and a linker between them.

The Significance of Chirality in Drug Design and Synthesis of Bitopic Ligands as D Receptor (DR) Selective Agonists.

Because of the large degree of homology among dopamine D-like receptors, discovering ligands capable of discriminating between the D, D, and D receptor subtypes remains a significant challenge. Previous work has exemplified the use of bitopic ligands as a powerful strategy in achieving subtype selectivity for agonists and antagonists alike. Inspired by the potential for chemical modification of the D preferential agonists (+)-PD128,907 () and PF592,379 (), we synthesized bitopic structures to further improve their DR selectivity.