JNJ-18038683

JNJ-18038683
Identifiers
	IUPAC name 1-benzyl-3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[3,4-d]azepine;
CAS Number	851373-91-6;
PubChem CID	11151899;
ChemSpider	9327007;
UNII	28PGH5X4OQ;
CompTox Dashboard (EPA)	DTXSID001336543 ;
Chemical and physical data
Formula	C20H20ClN3
Molar mass	337.85 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1CNCCC2=C1C(=NN2CC3=CC=CC=C3)C4=CC=C(C=C4)Cl;
	InChI InChI=1S/C20H20ClN3/c21-17-8-6-16(7-9-17)20-18-10-12-22-13-11-19(18)24(23-20)14-15-4-2-1-3-5-15/h1-9,22H,10-14H2; Key:UKJPMZGILXATGT-UHFFFAOYSA-N;

JNJ-18038683 is a potent and selective antagonist of the 5HT₇ serotonin receptor discovered by Johnson & Johnson. It has nootropic and antidepressant effects in both animal and human studies and has progressed to Phase II trials as an adjunctive treatment for improving cognition and mood in stable bipolar disorder; it has been found to reduce REM sleep (the lightest stage of sleep, elevated in depression) in humans and block circadian rhythm phase-shift advances in mice.^[1]^[2]

It binds to the 5-HT6 serotonin receptor with 10x less affinity.^[3] At relevant doses, inhibition of 5-HT6 would be expected to render pro-cognitive and anti-dementia effects.^[4]^[5]

References

^ Bonaventure P, Dugovic C, Kramer M, De Boer P, Singh J, Wilson S, et al. (August 2012). "Translational evaluation of JNJ-18038683, a 5-hydroxytryptamine type 7 receptor antagonist, on rapid eye movement sleep and in major depressive disorder". The Journal of Pharmacology and Experimental Therapeutics. 342 (2): 429–40. doi:10.1124/jpet.112.193995. PMID 22570363. S2CID 10418102.
^ Shelton J, Yun S, Losee Olson S, Turek F, Bonaventure P, Dvorak C, et al. (2014). "Selective pharmacological blockade of the 5-HT7 receptor attenuates light and 8-OH-DPAT induced phase shifts of mouse circadian wheel running activity". Frontiers in Behavioral Neuroscience. 8: 453. doi:10.3389/fnbeh.2014.00453. PMC 4295543. PMID 25642174.
^ "JNJ-18038683 FREE BASE". www.chemsrc.com. Retrieved 2022-01-07.
^ Andrews, Megan; Tousi, Babak; Sabbagh, Marwan N. (June 2018). "5HT6 Antagonists in the Treatment of Alzheimer's Dementia: Current Progress". Neurology and Therapy. 7 (1): 51. doi:10.1007/s40120-018-0095-y. PMID 29728891.
^ González-Vera, Juan A.; Medina, Rocío A.; Martín-Fontecha, Mar; Gonzalez, Angel; de la Fuente, Tania; Vázquez-Villa, Henar; García-Cárceles, Javier; Botta, Joaquín; McCormick, Peter J.; Benhamú, Bellinda; Pardo, Leonardo (2017-01-24). "A new serotonin 5-HT6 receptor antagonist with procognitive activity – Importance of a halogen bond interaction to stabilize the binding". Scientific Reports. 7 (1): 41293. doi:10.1038/srep41293. ISSN 2045-2322.

[pmid22570363-1] Bonaventure P, Dugovic C, Kramer M, De Boer P, Singh J, Wilson S, et al. (August 2012). "Translational evaluation of JNJ-18038683, a 5-hydroxytryptamine type 7 receptor antagonist, on rapid eye movement sleep and in major depressive disorder". The Journal of Pharmacology and Experimental Therapeutics. 342 (2): 429–40. doi:10.1124/jpet.112.193995. PMID 22570363. S2CID 10418102.

[pmid25642174-2] Shelton J, Yun S, Losee Olson S, Turek F, Bonaventure P, Dvorak C, et al. (2014). "Selective pharmacological blockade of the 5-HT7 receptor attenuates light and 8-OH-DPAT induced phase shifts of mouse circadian wheel running activity". Frontiers in Behavioral Neuroscience. 8: 453. doi:10.3389/fnbeh.2014.00453. PMC 4295543. PMID 25642174.

[3] "JNJ-18038683 FREE BASE". www.chemsrc.com. Retrieved 2022-01-07.

[4] Andrews, Megan; Tousi, Babak; Sabbagh, Marwan N. (June 2018). "5HT6 Antagonists in the Treatment of Alzheimer's Dementia: Current Progress". Neurology and Therapy. 7 (1): 51. doi:10.1007/s40120-018-0095-y. PMID 29728891.

[5] González-Vera, Juan A.; Medina, Rocío A.; Martín-Fontecha, Mar; Gonzalez, Angel; de la Fuente, Tania; Vázquez-Villa, Henar; García-Cárceles, Javier; Botta, Joaquín; McCormick, Peter J.; Benhamú, Bellinda; Pardo, Leonardo (2017-01-24). "A new serotonin 5-HT6 receptor antagonist with procognitive activity – Importance of a halogen bond interaction to stabilize the binding". Scientific Reports. 7 (1): 41293. doi:10.1038/srep41293. ISSN 2045-2322.

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