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Structure-based Design of Selective Serotonin Biased Agonists as Chemical Probes for Psychedelic Potential

Award Number: R01MH133849
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/12/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Structure-based Design of Selective Serotonin Biased Agonists as Chemical Probes for Psychedelic Potential - Project Summary: Psychedelics have shown extraordinary promise as fast-acting and long-lasting anti-depressants, but few selective agonists exist for the 5-HT2A receptor, which is the principal target for induction of psychedelic effects in humans. Many lingering questions remain as to the receptor profile needed to produce anti-depressant effects versus psychedelic effects, and whether these effects can be dissociated to yield effective non- psychedelic anti-depressants with 5-HT2A agonism. Our preliminary data reveals that many of the prototypical psychedelics are not selective for the 5-HT2A receptor. Therefore, the study of psychedelics alone is insufficient to answer these long-standing questions and instead deserve a probe-based approach. This project seeks to develop novel chemical probes to address the problems of i) 5-HT receptor selectivity and ii) pathway-selective or biased agonism at the 5-HT2A receptor. Our preliminary data suggests that superior 5-HT2A-selective agonists, and 5-HT2A/5-HT1B/1D mixed agonists can be designed using a structure-based approach. In Aim 1, we will explore conformationally-restricted N-benzyl analogs to achieve optimal 5-HT2A selectivity and engineer in substitutions to drive biased agonism. Aim 2, we will utilize a rationally-designed privileged scaffold that shows promise as a 5-HT2A/5-HT1B/1D selective agonist, and engineer in substitutions designed to drive ligand bias. Finally, in Aim 3, we will use the 5-HT1B/1D/1F-selective triptan scaffold to engineer in substitutions to cause shifts in biased agonism at these receptor subtypes. Overall, this project aims to generate selective 5-HT receptor biased and balanced agonist probe pairs, which will available to the research community for the interrogation of psychedelic versus anti-depressant potential. Ultimately, this project will initiate novel treatment strategies for mental health issues and usher in a new era of serotonin drug discovery. 1


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $516,972 )
2026	2026	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Mental Health Research Grants	000	4	3/23/2026	NON-COMPETING CONTINUATION	$516,972
														Subtotal = $516,972

Issue Date FY: 2025 ( Subtotal = $516,972 )
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Mental Health Research Grants	001	3	9/22/2025	NON-COMPETING CONTINUATION	$77,546
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Mental Health Research Grants	000	3	4/14/2025	NON-COMPETING CONTINUATION	$439,426
														Subtotal = $516,972

Issue Date FY: 2024 ( Subtotal = $516,972 )
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Mental Health Research Grants	000	2	4/5/2024	NON-COMPETING CONTINUATION	$465,275
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Mental Health Research Grants	001	2	8/15/2024	NON-COMPETING CONTINUATION	$51,697
														Subtotal = $516,972

Issue Date FY: 2023 ( Subtotal = $530,972 )
2023	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Mental Health Research Grants	000	1	7/12/2023	NEW	$530,972
														Subtotal = $530,972

Grand Total All Awards = $2,081,888

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Structure-based Design of Selective Serotonin Biased Agonists as Chemical Probes for Psychedelic Potential

Award Number: R01MH133849

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/12/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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