Friday, November 22, 2024 11/22/2024

Synthesis and in vitro and in vivo screening of fused and tethered heterocyclic peptidomimetics for the discovery of new analgesics with decreased side effects

Award Number: R33DA044425
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Abstract

We hypothesize that the development of peripherally-restricted, mixed-activity opioid receptor agonists will produce robust analgesia while exhibiting reduced side effects, including a lack of respiratory depression or reinforcing properties. In preliminary studies, the in vitro screening of novel bis-imidazolidines and fused heterocyclic lead compounds BIM-22 and FDC-14 identified mixed-opioid receptor agonist activity. After peripheral (i.p.) administration to mice, both compounds demonstrated antinociception equivalent to morphine in the 55oC warm-water tail withdrawal (tail-flick) assay, but FDC-14 was 25 times more potent than morphine in the acetic acid writhing test, with an antinociceptive potency ratio of 72.7, suggestive of peripherally- restricted activity. Confirming this, LC-MS/MS studies detected BIM-22 and FDC-14 in harvested mouse blood, but not brain, after i.v. administration. This proposal addresses two research areas of particular interest for this FOA: i) The development of new and innovative molecular probes for receptors and new strategies for innovative peptidomimetic design, and ii) The identification of structurally diverse, orally active, metabolically stable peripherally-restricted opioid agonists. We propose six interacting aims: In Aim 1, we propose the computationally guided synthesis of heterocyclic peptidomimetics: bis-imidazolidin-2-imines, piperazines, bis- piperazine, bis-imidazolone and fused heterocyclic libraries. In Aim 2, we will screen all compounds in competition radioligand binding assays to determine affinity for μ- (MOR), δ- (DOR), and κ- (KOR) opioid receptors, and in functional assays to identify dual δ/κ or dual δ/µ agonists. In Aim 3, ten selected compounds will be evaluated in vitro for pharmacokinetic properties and screened in vivo for antinociception using the mouse tail-flick assay. Lead compounds identified from this aim will guide 2nd generation SAR studies to enhance peripherally-selective activity. In Aim 4: we will perform full in vivo antinociceptive characterization of lead agonist compounds. The most stable, active 4 agonists not crossing the BBB in Aims 2+3 will be evaluated after i.p. administration with mouse tail-flick and acetic-acid writhing assays for efficacy, duration of action, and opioid receptor selectivity. In Aim 5: we will characterize the bioavailability in mice of the selected 4 agonists following oral administration and confirm their inability to penetrate the blood brain barrier. In Aim 6: The two most potent bioavailable novel agonists identified in Aims 1-5 will be examined for liabilities, specifically antinociceptive tolerance, respiratory and hyperlocomotor effects in the CLAMS physiological and behavioral assessment system, sedation and disruption of coordinated locomotor activity in the rotorod assay, and assessment for rewarding or aversive effects in the conditioned place preference (CPP) assay. Effects on GI transit will also be evaluated to assess effects on constipation. In summary, we expect to generate novel peripherally-restricted, mixed-activity peptidomimetic opioid receptor agonists as both probes and analgesics with reduced side effects, thereby significantly impacting analgesic development.


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: 2024 ( Subtotal = $0 )
2024	2022	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	000	5	11/1/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = -$68,259 )
2023	2020	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES, INC.	11350 SW VILLAGE PKWY	PORT SAINT LUCIE	FL	34987	SAINT LUCIE	USA	Drug Use and Addiction Research Programs	000	2	3/13/2023	EXTENSION WITH OR WITHOUT FUNDS	-$68,259
														Subtotal = -$68,259

Issue Date FY: 2022 ( Subtotal = $297,085 )
2022	2022	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	000	5	11/9/2021	NON-COMPETING CONTINUATION	$267,377
2022	2022	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	001	5	3/25/2022	NON-COMPETING CONTINUATION	$29,708
														Subtotal = $297,085

Issue Date FY: 2021 ( Subtotal = $304,664 )
2021	2021	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Abuse and Addiction Research Programs	001	4	2/19/2021	NON-COMPETING CONTINUATION	$30,467
2021	2021	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Abuse and Addiction Research Programs	000	4	11/5/2020	NON-COMPETING CONTINUATION	$274,197
														Subtotal = $304,664

Issue Date FY: 2020 ( Subtotal = $391,639 )
2020	2020	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES, INC.	11350 SW VILLAGE PKWY	PORT SAINT LUCIE	FL	34987	SAINT LUCIE	USA	Drug Abuse and Addiction Research Programs	001	2	3/27/2020	EXTENSION WITH OR WITHOUT FUNDS	$71,481
2020	2020	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES, INC.	11350 SW VILLAGE PKWY	PORT SAINT LUCIE	FL	34987	SAINT LUCIE	USA	Drug Abuse and Addiction Research Programs	000	2	12/12/2019	EXTENSION WITH OR WITHOUT FUNDS	$380,480
2020	2020	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES, INC.	11350 SW VILLAGE PKWY	PORT SAINT LUCIE	FL	34987	SAINT LUCIE	USA	Drug Abuse and Addiction Research Programs	002	2	5/7/2020	EXTENSION WITH OR WITHOUT FUNDS	-$377,257
2020	2020	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Abuse and Addiction Research Programs	005	3	6/2/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$3,223
2020	2020	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES, INC.	11350 SW VILLAGE PKWY	PORT SAINT LUCIE	FL	34987	SAINT LUCIE	USA	Drug Abuse and Addiction Research Programs	004	2	6/2/2020	EXTENSION WITH OR WITHOUT FUNDS	-$3,223
2020	2020	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Abuse and Addiction Research Programs	003	3	5/7/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$316,935
														Subtotal = $391,639

Grand Total All Awards = $925,129

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Synthesis and in vitro and in vivo screening of fused and tethered heterocyclic peptidomimetics for the discovery of new analgesics with decreased side effects

Award Number: R33DA044425

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer