Mechanism of Action and Structure–Activity Relationships of Tetracyclic Small Molecules Acting as Universal Positive Allosteric Modulators of the Cholecystokinin Receptor
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Methods
3. Results
4. Discussion
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Receptor-Ligands | pEC50 | n, p Values |
---|---|---|
CCK1R | ||
CCK-8 | 10.6 ± 0.1 | 5 |
CCK-8 + “hit 1” | 11.1 ± 0.1 * | 5, 0.048 |
CCK-8 + “hit 6” | 11.5 ± 0.2 ** | 5, 0.002 |
CCK1R | ||
CCK-33 | 9.6 ± 0.2 | 5 |
CCK-33 + “hit 1” | 10.7 ± 0.2 * | 5, 0.016 |
CCK-33 + “hit 6” | 10.7 ± 0.2 ** | 5, 0.008 |
CCK2R | ||
CCK-8 | 9.3 ± 0.1 | 6 |
CCK-8 + “hit 1” | 9.5 ± 0.1 | 6, 0.20 |
CCK-8 + “hit 6” | 9.5 ± 0.1 | 6, 0.19 |
CCK1R(Y140A) | ||
CCK-8 | 9.0 ± 0.1 | 5 |
CCK-8 + “hit 1” | 9.7 ± 0.1 *** | 5, 0.0008 |
CCK-8 + “hit 6” | 10 ± 0.1 *** | 5, <0.0001 |
CCK1R | ||
CCK-OPE | 7.3 ± 0.2 | 5 |
CCK-OPE + “hit 1” | 8.0 ± 0.2 | 5, 0.08 |
CCK-OPE + “hit 6” | 8.1 ± 0.2 * | 6, 0.04 |
CCK1R + excess cholesterol | ||
CCK-8 | 9.4 ± 0.2 | 5 |
CCK-8 + “hit 1” | 10.2 ± 0.2 ** | 5, 0.005 |
CCK-8 + “hit 6” | 10.2 ± 0.2 ** | 6, 0.005 |
CCK-8 | n | CCK-8 + “Hit 1” | n, p Values | CCK-8 + “Hit 6” | n, p Values | |
---|---|---|---|---|---|---|
Kon rate, × 108 M−1 min−1 | 0.7 ± 0.1 | 5 | 2.6 ± 0.6 * | 3, 0.04 | 0.7 ± 0.4 | 5, 0.31 |
Koff rate, min−1 | 1.1 ± 0.1 | 5 | 0.4 ± 0.1 * | 3, 0.04 | 0.5 ± 0.1 ** | 5, 0.01 |
pKi | 7.8 ± 0.1 | 5 | 8.8 ± 0.1 * | 3, 0.04 | 8.1 ± 0.2 | 5, 0.06 |
CCK-8 + “Hit 1” | CCK-8 + “Hit 6” | |
---|---|---|
pKb | 4.5 ± 0.4 | 4.6 ± 0.2 |
Tau Kb | 0.5 ± 0.1 | 0.4 ± 0.1 |
Logαβ | 1.5 ± 0.3 | 1.0 ± 0.2 |
n | 5 | 5 |
ID | Structure | CCK1R PAM (IP-One) | CCK1R Ago (IP-One) | AVP2R PAM (cAMP) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
R1 | R2 | A | X | Y | EC50 (µM) | Emax (%) | Score | EC50 (µM) | Emax (%) | Score | EC50 (µM) | Emax (%) | Score | |
CMP-40 | cyclohexyl | S | C | 0 | 0 | 0 | 0 | 0 | 0 | 2.9 ± 0.1 | 96 ± 9 | 5.33 | ||
CMP-41 | cyclohexyl | S | C | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
CMP-65 | cyclohexyl | S | C | 0 | 0 | 0 | 0 | 0 | 0 | 10.0 ± 1.7 | 96 ± 5 | 4.78 | ||
CMP-42 | cyclohexyl | S | C | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
CMP-44 | cyclohexyl | S | C | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
CMP-45 | cyclohexyl | S | C | 0 | 0 | 0 | 0 | 0 | 0 | 37.9 ± 7.0 | 33 ± 13 | 1.46 | ||
CMP-64 | cyclohexyl | S | C | N.D. | N.D. | N.D. | 0 | 0 | 0 | 0 | 0 | 0 | ||
CMP-46 | cyclohexyl | S | C | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
CMP-47 | cyclohexyl | S | C | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
CMP-48 | cyclohexyl | S | C | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
CMP-49 | cyclohexyl | S | C | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
CMP-50 | cyclohexyl | S | C | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
CMP-51 | cyclohexyl | S | C | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
CMP-52 | cyclohexyl | S | N | 0 | 0 | 0 | 0 | 0 | 0 | N.D. | N.D. | N.D. | ||
CMP-59 | cyclohexyl | S | C | N.D. | N.D. | N.D. | 0 | 0 | 0 | 22.3 ± 7.2 | 20 ± 0 | 0.93 |
ID | Structure | CCK1R PAM (IP-One) | CCK1R Ago (IP-One) | AVP2R PAM (cAMP) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
R1 | R2 | A | X | Y | EC50 (µM) | Emax (%) | Score | EC50 (µM) | Emax (%) | Score | EC50 (µM) | Emax (%) | Score | |
CMP-56 | cyclopentyl | S | C | N.D. | N.D. | N.D. | 0 | 0 | 0 | 0 | 0 | 0 | ||
CMP-57 | cyclohexyl | S | C | N.D. | N.D. | N.D. | 0 | 0 | 0 | 0 | 0 | 0 | ||
CMP-58 | cyclohexyl | O | C | N.D. | N.D. | N.D. | 0 | 0 | 0 | 0 | 0 | 0 | ||
CMP-60 | cyclohexyl | O | C | N.D. | N.D. | N.D. | 0 | 0 | 0 | 0 | 0 | 0 | ||
CMP-38 | cyclohexyl | S | C | 7.6 ± 3.3 | 20 ± 7.6 | 1.01 | 0 | 0 | 0 | 0 | 0 | 0 | ||
CMP-62 | cyclopentyl | O | C | N.D. | N.D. | N.D. | 0 | 0 | 0 | 0 | 0 | 0 | ||
CMP-39 | cyclohexyl | O | C | N.D. | N.D. | N.D. | 0 | 0 | 0 | 0 | 0 | 0 | ||
CMP-63 | cyclopentyl | O | C | N.D. | N.D. | N.D. | 0 | 0 | 0 | 0 | 0 | 0 | ||
CMP-55 | cyclohexyl | O | C | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
CMP-53 | cyclohexyl | O | C | 0 | 0 | 0 | 0 | 0 | 0 | 15.3 ± 9.8 | 61 ± 12 | 2.95 |
ID | Structure | CCK1R PAM (IP-One) | CCK1R ago (IP-One) | AVP2R PAM (cAMP) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
R1 | R2 | A | X | Y | EC50 (µM) | Emax (%) | Score | EC50 (µM) | Emax (%) | Score | EC50 (µM) | Emax (%) | Score | |
CMP-5 | cyclopentyl | S | C | 7.5 ± 2.9 | 53 ± 6 | 2.66 | N.D. | N.D. | N.D. | 8.1 ± 8.5 | 32 ± 11 | 1.61 | ||
CMP-7 | cyclohexyl | S | C | 8.0 ± 2.1 | 48 ± 11 | 2.39 | 0 | 0 | 0 | 6.5 ± 4.2 | 31 ± 2 | 1.61 | ||
CMP-8 | cyclohexyl | S | C | 37.8 ± 3.9 | 53 ± 1 | 2.34 | 0 | 0 | 0 | 15.7 ± 8.4 | 48 ± 12 | 2.31 | ||
CMP-12 | cyclohexyl | O | C | 14.1 ± 4.3 | 46 ± 7 | 2.23 | N.D. | N.D. | N.D. | 11.4 ± 3.6 | 66 ± 3 | 3.28 | ||
CMP-18 | cyclohexyl | S | C | 12.7 ± 5.5 | 43 ± 21 | 1.96 | 0 | 0 | 0 | 11.8 ± 14.0 | 40 ± 17 | 1.99 | ||
CMP-28 (“hit 6”) | cyclohexyl | O | C | 9.5 ± 3.5 | 35 ± 13 | 1.66 | N.D. | N.D. | N.D. | 15.0 ± 13.6 | 73 ± 16 | 3.53 | ||
CMP-30 | cyclohexyl | O | C | 27.1 ± 10.7 | 36 ± 16 | 1.55 | 0 | 0 | 0 | 5.9 ± 3.8 | 29 ± 0 | 1.52 | ||
CMP-32 | cyclohexyl | S | C | 23.9 ± 25.8 | 41 ± 34 | 1.52 | 0 | 0 | 0 | 9.3 ± 11.1 | 33 ± 26 | 1.67 | ||
CMP-36 | cyclohexyl | O | C | 3.3 ± 5.4 | 25 ± 10 | 1.32 | 0 | 0 | 0 | 6.1 ± 2.8 | 27 ± 20 | 1.41 | ||
CMP-61 | cyclohexyl | S | C | N.D. | N.D. | N.D. | 0 | 0 | 0 | 0 | 0 | 0 |
ID | Structure | CCK1R PAM (IP-One) | CCK1R ago (IP-One) | AVP2R PAM (cAMP) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
R1 | R2 | A | X | Y | EC50 (µM) | Emax (%) | Score | EC50 (µM) | Emax (%) | Score | EC50 (µM) | Emax (%) | Score | |
CMP-10 | cyclopentyl | O | C | 22.5 ± 9.0 | 51 ± 16 | 2.28 | N.D. | N.D. | N.D. | 21.7 ± 11.3 | 46 ± 9 | 2.15 | ||
CMP-13 | cyclopentyl | O | C | 11.2 ± 4.2 | 52 ± 36 | 2.23 | 0 | 0 | 0 | 12.6 ± 7.9 | 28 ± 14 | 1.35 | ||
CMP-15 | cyclohexyl | O | C | 17.8 ± 6.2 | 43 ± 3 | 2.04 | 0 | 0 | 0 | 7.3 ± 3.3 | 58 ± 15 | 2.97 | ||
CMP-20 | cyclopentyl | O | C | 23.6 ± 1.0 | 42 ± 12 | 1.90 | 0 | 0 | 0 | 21.2 ± 19.7 | 25 ± 1 | 1.17 | ||
CMP-21 | cyclopentyl | O | C | 23.8 ± 10.5 | 45 ± 23 | 1.90 | 0 | 0 | 0 | 22.8 ± 3.8 | 37 ± 4 | 1.74 | ||
CMP-24 | cyclopentyl | O | C | 12.7 ± 15.5 | 48 ± 45 | 1.81 | 0 | 0 | 0 | 19.6 ± 5.1 | 34 ± 23 | 1.62 | ||
CMP-25 | cyclohexyl | O | C | 14.5 ± 5.3 | 38 ± 11 | 1.79 | N.D. | N.D. | N.D. | 8.6 ± 5.4 | 74 ± 12 | 3.75 | ||
CMP-33 | cyclopentyl | O | C | 18.8 ± 7.7 | 35 ± 19 | 1.51 | 0 | 0 | 0 | 21.0 ± 6.5 | 34 ± 1 | 1.60 | ||
CMP-34 | cyclohexyl | S | C | 29.0 ± 13.1 | 34 ± 13 | 1.50 | 0 | 0 | 0 | 7.8 ± 4.0 | 42 ± 17 | 2.13 | ||
CMP-54 | cyclohexyl | S | C | N.D. | N.D. | N.D. | 0 | 0 | 0 | 26.2 ± 2.4 | 43 ± 7 | 1.96 |
ID | Structure | CCK1R PAM (IP-One) | CCK1R ago (IP-One) | AVP2R PAM (cAMP) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
R1 | R2 | A | X | Y | EC50 (µM) | Emax (%) | Score | EC50 (µM) | Emax (%) | Score | EC50 (µM) | Emax (%) | Score | |
CMP-6 | cyclohexyl | S | C | 13.8 ± 3.2 | 57 ± 27 | 2.58 | 0 | 0 | 0 | 9.9 ± 0.5 | 33 ± 1 | 1.67 | ||
CMP-11 | cyclohexyl | S | C | 9.1 ± 4.8 | 45 ± 6 | 2.27 | 27.1 ± 15.3 | 21 ± 2 | 0.96 | 3.2 ± 1.1 | 44 ± 8 | 2.44 | ||
CMP-14 | cyclohexyl | S | C | 8.9 ± 1.7 | 44 ± 10 | 2.17 | 29.7 ± 8.0 | 17 ± 5 | 0.72 | 4.7 ± 4.1 | 56 ± 33 | 2.97 | ||
CMP-22 | cyclohexyl | S | C | 12.2 ± 4.6 | 39 ± 11 | 1.87 | 26.9 ± 1.1 | 60 ± 4.5 | 2.76 | 2.7 ± 0.7 | 52 ± 4 | 2.92 | ||
CMP-23 | cyclohexyl | S | N | 9.6 ± 3.6 | 38 ± 13 | 1.86 | 30.0 ± 4.9 | 41 ± 1 | 1.85 | 3.1 ± 1.3 | 53 ± 3 | 2.93 | ||
CMP-26 | cyclohexyl | S | C | 30.2 ± 11.2 | 41 ± 15 | 1.76 | N.D. | N.D. | N.D. | 3.7 ± 0.5 | 16 ± 4 | 0.87 | ||
CMP-27 | cyclohexyl | S | N | 18.4 ± 8.1 | 38 ± 14 | 1.70 | 0 | 0 | 0 | 9.1 ± 1.0 | 70 ± 4 | 3.51 | ||
CMP-29 | 4-methyl | S | C | 15.1 ± 1.8 | 33 ± 7 | 1.59 | 52.9 ± 39 | 39 ± 12 | 1.67 | 19.2 ± 0.8 | 35 ± 0 | 1.66 | ||
CMP-31 | cyclohexyl | S | C | 29.6 ± 1.8 | 35 ± 14 | 1.54 | 0 | 0 | 0 | 5.4 ± 1.7 | 24 ± 3 | 1.26 | ||
CMP-35 | cyclohexyl | S | C | 31.3 ± 14.9 | 36 ± 20 | 1.49 | 0 | 0 | 0 | 7.9 ± 2.5 | 31 ± 0 | 1.59 | ||
CMP-37 | cyclopentyl | S | C | 31.7 ± 1.2 | 28 ± 9 | 1.26 | 0 | 0 | 0 | 0 | 0 | 0 |
ID | Structure | CCK1R PAM (IP-One) | CCK1R Ago (IP-One) | AVP2R PAM (cAMP) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
R1 | R2 | A | X | Y | EC50 (µM) | Emax (%) | Score | EC50 (µM) | Emax (%) | Score | EC50 (µM) | Emax (%) | Score | |
CMP-1 (“hit 1”) | cyclohexyl | S | C | 12.8 ± 4.6 | 63 ± 18 | 2.94 | N.D. | N.D. | N.D. | 12.0 ± 7.1 | 20.7 ± 9.8 | 1.02 | ||
CMP-2 | dimethyl thiacyclohe-xyl | S | C | 9.2 ± 2.0 | 57 ± 12 | 2.82 | 31.3 ± 3.1 | 31 ± 15 | 1.31 | N.D. | N.D. | N.D. | ||
CMP-3 | cyclohexyl | S | C | 16.6 ± 15.9 | 60 ± 23 | 2.77 | N.D. | N.D. | N.D. | 14.8 ± 10.3 | 34.0 ± 5.3 | 1.64 | ||
CMP-4 | cyclohexyl | S | C | 14.4 ± 1.5 | 62 ± 33 | 2.71 | 0 | 0 | 0 | 12.8 ± 14.0 | 24.5 ± 7.1 | 1.20 | ||
CMP-9 | dimethyl thiacyclohe-xyl | S | C | 9.3 ± 1.1 | 46 ± 3 | 2.31 | N.D. | N.D. | N.D. | N.D. | N.D. | N.D. | ||
CMP-16 | methyl | S | C | 32.6 ± 12.5 | 45 ± 7 | 2.02 | 0 | 0 | 0 | 7.6 ± 8.2 | 17 ± 4 | 0.87 | ||
CMP-17 | cyclohexyl | S | N | 23.0 ± 17.9 | 50 ± 32 | 1.99 | N.D. | N.D. | N.D. | 22.4 ± 9.2 | 26 ± 1 | 1.20 | ||
CMP-19 | cyclohexyl | S | C | 18.2 ± 8.6 | 51 ± 43 | 1.94 | 0 | 0 | 0 | N.D. | N.D. | N.D. | ||
CMP-43 | cyclopentyl | S | C | N.D. | N.D. | N.D. | 0 | 0 | 0 | N.D. | N.D. | N.D. |
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Dengler, D.G.; Harikumar, K.G.; Yen, A.; Sergienko, E.A.; Miller, L.J. Mechanism of Action and Structure–Activity Relationships of Tetracyclic Small Molecules Acting as Universal Positive Allosteric Modulators of the Cholecystokinin Receptor. Membranes 2023, 13, 150. https://doi.org/10.3390/membranes13020150
Dengler DG, Harikumar KG, Yen A, Sergienko EA, Miller LJ. Mechanism of Action and Structure–Activity Relationships of Tetracyclic Small Molecules Acting as Universal Positive Allosteric Modulators of the Cholecystokinin Receptor. Membranes. 2023; 13(2):150. https://doi.org/10.3390/membranes13020150
Chicago/Turabian StyleDengler, Daniela G., Kaleeckal G. Harikumar, Alice Yen, Eduard A. Sergienko, and Laurence J. Miller. 2023. "Mechanism of Action and Structure–Activity Relationships of Tetracyclic Small Molecules Acting as Universal Positive Allosteric Modulators of the Cholecystokinin Receptor" Membranes 13, no. 2: 150. https://doi.org/10.3390/membranes13020150