TY - JOUR
T1 - New dual 5-HT1A and 5-HT7 receptor ligands derived from SYA16263
AU - Ofori, Edward
AU - Onyameh, Edem K.
AU - Gonela, Uma M.
AU - Voshavar, Chandrashekhar
AU - Bricker, Barbara
AU - Swanson, Tracy L.
AU - Eshleman, Amy J.
AU - Schmachtenberg, Jennifer L.
AU - Bloom, Shelley H.
AU - Janowsky, Aaron J.
AU - Ablordeppey, Seth Y.
N1 - Publisher Copyright:
© 2021
PY - 2021/3/15
Y1 - 2021/3/15
N2 - We have previously reported that dual 5-HT1A and 5-HT7 receptor ligands might find utility as treatment options for various CNS related conditions including cognitive and anxiolytic impairments. We have also more recently reported that SYA16263 has antipsychotic-like properties with an absence of catalepsy in animal models ascribed to its ability to recruit β-arrestin to the D2 receptor. However, SYA16263 also binds with very high affinity to 5-HT1AR (Ki = 1.1 nM) and a moderate affinity at 5-HT7R (Ki = 90 nM). Thus, it was of interest to exploit its pharmacophore elements in designing new dual receptor ligands. Using SYA16263 as the lead molecule, we have conducted a limited structure-affinity relationship (SAFIR) study by modifying various structural elements in the arylalkyl moiety, resulting in the identification of a new dual 5-HT1AR and 5-HT7R ligand, 6-chloro-2-methyl-2-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-2,3-dihydro-1H-inden-1-one (21), which unlike SYA16263, has a sub-nanomolar (5-HT1AR, Ki = 0.74 nM) and a low nanomolar (5-HT7R, Ki = 8.4 nM) affinity for these receptors. Interestingly, 21 is a full agonist at 5-HT1AR and antagonist at the 5-HT7R, functional characteristics which point to its potential as an antidepressant agent.
AB - We have previously reported that dual 5-HT1A and 5-HT7 receptor ligands might find utility as treatment options for various CNS related conditions including cognitive and anxiolytic impairments. We have also more recently reported that SYA16263 has antipsychotic-like properties with an absence of catalepsy in animal models ascribed to its ability to recruit β-arrestin to the D2 receptor. However, SYA16263 also binds with very high affinity to 5-HT1AR (Ki = 1.1 nM) and a moderate affinity at 5-HT7R (Ki = 90 nM). Thus, it was of interest to exploit its pharmacophore elements in designing new dual receptor ligands. Using SYA16263 as the lead molecule, we have conducted a limited structure-affinity relationship (SAFIR) study by modifying various structural elements in the arylalkyl moiety, resulting in the identification of a new dual 5-HT1AR and 5-HT7R ligand, 6-chloro-2-methyl-2-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-2,3-dihydro-1H-inden-1-one (21), which unlike SYA16263, has a sub-nanomolar (5-HT1AR, Ki = 0.74 nM) and a low nanomolar (5-HT7R, Ki = 8.4 nM) affinity for these receptors. Interestingly, 21 is a full agonist at 5-HT1AR and antagonist at the 5-HT7R, functional characteristics which point to its potential as an antidepressant agent.
KW - 5-HT subtype Receptors
KW - Dopamine and serotonin receptors
KW - Dual 5-HT and 5-HT receptors
KW - Indanones
KW - Pyridinyl piperazine
KW - SYA16263
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UR - http://www.scopus.com/inward/citedby.url?scp=85100758953&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2021.113243
DO - 10.1016/j.ejmech.2021.113243
M3 - Article
C2 - 33582388
AN - SCOPUS:85100758953
SN - 0223-5234
VL - 214
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 113243
ER -