Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D₂ Receptor Through Fragmentation of a Bitopic Ligand

Abstract

(2015) Discovery of a novel class of negative allosteric modulator of the dopamine D2 receptor through fragmentation of a bitopic ligand. Journal of Medicinal Chemistry, 58 (17). pp. 6819-6843. ISSN 0022-2623 Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/30315/1/jm-2015-005859.R2%20-%20JMC %2058%2817%29%202015%206819.pdf Copyright and reuse:The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions. This article is made available under the University of Nottingham End User licence and may be reused according to the conditions of the licence. For more details see: http://eprints.nottingham.ac.uk/end_user_agreement.pdf A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ABSTRACT Recently, we have demonstrated that N- ((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H) 'allosteric lead', we designed and synthesised an extensive fragment library to generate novel SAR and identify N-butyl-1H-indole-2-carboxamide (11d), which displayed both increased negative cooperativity and affinity for the D 2 R. These data illustrate that fragmentation of extended compounds can expose fragments with purely allosteric pharmacology.

Highly Selective Dopamine D3 Receptor (D3R) Antagonists and Partial Agonists Based on Eticlopride and the D3R Crystal Structure: New Leads for Opioid Dependence Treatment

“…22 In the present study, no attempt to elucidate allosterism at D 3 R was made, but it is intriguing to consider that depending on the PP, these molecules may show a bitopic profile. Identifying the structural determinants of these potentially bitopic agents will be of future interest.…”

Synthesis and Pharmacological Characterization of Novel trans-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity and Allosteric Pharmacology at the Dopamine D3 Receptor (D3R)

“…15 Notably, however, in a previous study, found that at concentrations over 50 μM, 13b acts as an allosteric antagonist of the D 2 R with modest negative cooperativity with dopamine. 27 Together, these results suggest that the SPs have either no activity at, or very low affinity for, these dopamine receptors when not linked to a PP.…”

“…13 As shown previously with other SPs, 13,15 13a-d showed no or very weak ability to displace [ 3 H]N-methylspiperone (NMS) binding from either the D 2 R or D 3 R. Notably, however, in a separate study, at concentrations over 50 μM, 13b was able to partially inhibit (~20%) [ 3 H]spiperone binding to the D 2 R, a finding that might be consistent with an allosteric interaction. 27 …”

Targeting multiple opioid receptors – improved analgesics with reduced side effects?

“…These findings suggest the simultaneous occupancy of δ receptors with an antagonist and μ receptors with an agonist as a promising strategy to dissociate antinociception from side effects. While there is no bitopic (dualsteric) compound so far for opioid receptors, this has been made for other class A GPCRs, for example, the M 1 muscarinic receptor agonist McN‐A‐343 (Valant et al , ) or the dopamine D 2 receptor agonist SB269652 (Mistry et al , ).…”