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.2015 Mar 18;6(3):476-84.
doi: 10.1021/cn500325v. Epub 2015 Jan 27.

The first structure-activity relationship studies for designer receptors exclusively activated by designer drugs

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The first structure-activity relationship studies for designer receptors exclusively activated by designer drugs

Xin Chen et al. ACS Chem Neurosci..

Abstract

Over the past decade, two independent technologies have emerged and been widely adopted by the neuroscience community for remotely controlling neuronal activity: optogenetics which utilize engineered channelrhodopsin and other opsins, and chemogenetics which utilize engineered G protein-coupled receptors (Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) and other orthologous ligand-receptor pairs. Using directed molecular evolution, two types of DREADDs derived from human muscarinic acetylcholine receptors have been developed: hM3Dq which activates neuronal firing, and hM4Di which inhibits neuronal firing. Importantly, these DREADDs were not activated by the native ligand acetylcholine (ACh), but selectively activated by clozapine N-oxide (CNO), a pharmacologically inert ligand. CNO has been used extensively in rodent models to activate DREADDs, and although CNO is not subject to significant metabolic transformation in mice, a small fraction of CNO is apparently metabolized to clozapine in humans and guinea pigs, lessening the translational potential of DREADDs. To effectively translate the DREADD technology, the next generation of DREADD agonists are needed and a thorough understanding of structure-activity relationships (SARs) of DREADDs is required for developing such ligands. We therefore conducted the first SAR studies of hM3Dq. We explored multiple regions of the scaffold represented by CNO, identified interesting SAR trends, and discovered several compounds that are very potent hM3Dq agonists but do not activate the native human M3 receptor (hM3). We also discovered that the approved drug perlapine is a novel hM3Dq agonist with >10 000-fold selectivity for hM3Dq over hM3.

Keywords: CNO; DREADD; SAR; hM3Dq; neuronal activation; perlapine.

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Figures

Figure 1
Figure 1
SAR studies of the CNO scaffold.
Scheme 1
Scheme 1. Synthesis of N4′-alkyl Substituted CNO Analogues
Reagents and conditions: (a)xylene, reflux, 48 h, 95% yield; (b) POCl3,N,N-dimethylaniline, toluene, 95 °C, 2 h, 67%yield; (c)N-alkylpiperazines, toluene, 120 °C,2 h, 69–80% yield; and (d)mCPBA, CH2Cl2, rt, 10 min, 65–75% yield.
Scheme 2
Scheme 2. Synthesis of Compounds6,7, and9–14
Reagentsand conditions: (a)CH3I, acetone, rt, overnight, 55% yield; (b) 2-oxypiperazine,1,4-dioxane/ethanol 1:1, 99 °C, overnight, 65% yield; (c) 1,3,8-triazaspiro[4.5]decane-2,4-dione(8), 1,4-dioxane/DMF (2:1), 130 °C, 24 h, 66% yield;(d) 1,2-dimethoxyethane, 0.5 N NaOH, microwave, 150 °C, 10 min,16% yield; (e) piperazine, toluene, 120 °C, 2 h, 69% yield; (f)AcCl, TEA, CH2Cl2, 0 °C, 1 h, 86% yield;(g) (1) LiAlD4, THF, N2, reflux, 2h, (2) CD3OD, 0 °C, (3) NH4OH, 0 °C, 84% yield;(h) MsCl, DIPEA, CH2Cl2, 0 °C, 1 h, 93%yield.
Scheme 3
Scheme 3. Synthesis of Compounds22–24
Reagents and conditions:(a)K2CO3, Cu, 3-methylbutan-1-ol, reflux, 4 h;(b) NaS2O4, NH4OH/H2O3:2, 80 °C, 30 min, 75% yield in two steps; (c) xylene, reflux,Dean–Stark conditions, 48 h, 96% yield; (d) POCl3,N,N-dimethylaniline, toluene,reflux, 3 h, 52% yield; (e) piperazine, toluene, reflux, overnight,63% yield; (f) 1-ethylpiperazine, toluene, reflux, 2 h, 72% yield;and (g)mCPBA, CH2Cl2, rt,10 min, 78% yield.
Figure 2
Figure 2
Compounds13 and21 are potent hM3Dqagonists and do not activate hM3 being similar to compound5a (CNO). The endogenous ligand acetylcholine (ACh), on the other hand,is a potent hM3 agonist and does not activate hM3Dq.
Figure 3
Figure 3
Perlapine is a potent full agonist of hM3Dqand does not activatehM3. CNO (compound5a) was used as a positive controlin the hM3Dq FLIPR assay, and acetylcholine (ACh) was used as a positivecontrol in the hM3 FLIPR assay.
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