Delving into the Latest Updates on SKF-82958 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

SKF-82958, SKF82958

Target

D1 receptor

Action

agonists

Mechanism

D1 receptor agonists(Dopamine D1 receptor agonists)

Therapeutic Areas

Nervous System DiseasesOther Diseases

Active Indication

Learning Disabilities

Inactive Indication

Parkinson Disease

Originator Organization

Smithkline Beecham Plc

Active Organization

Queen's University

Inactive Organization

Smithkline Beecham Plc

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC19H20ClNO2

InChIKeyHJWHHQIVUHOBQN-UHFFFAOYSA-N

CAS Registry80751-65-1

Eye-blinking has been used to catalog dopaminergic receptor subtype activation in several mammalian species. In this study, the dissimilar effects of directly-acting D₁ and D₂ agonists and an indirectly-acting non-selective agonist (SKF-82958, quinelorane, cocaine, respectively) on eye-blinking were confirmed in marmosets. Subsequently, functional magnetic resonance imaging (fMRI) was used to examine their effects on functional connectivity (FC) between the dopamine-rich putamen and other brain regions. Results indicate that SKF-82958 produced dose-dependent increases in blinking, with the highest dose (0.3 mg/kg) yielding > 9-fold increases over baseline values. In contrast, the highest dose of quinelorane (0.001 mg/kg) reduced blink rates to ∼30 % of baseline. Following the highest dose of cocaine (5.6 mg/kg), only limited (∼20 %) and short-lived (∼20-min) decreases in eye-blinking were observed. In fMRI studies, cocaine induced transient FC increases between putamen and striatal regions, whereas the D₁ and D₂ agonists induced distinct temporal dynamics and region-specific changes in putamen FC. SKF-82958 strengthened putamen FC with motor and sensory regions and reduced FC with visual and cerebellar regions. Conversely, quinelorane reduced putamen connectivity with motor and sensory areas and strengthened FC with regions associated with visual and emotional regulation. These effects in marmosets align with previous outcomes and show that dopamine receptor-subtype activation produce distinct patterns of FC between the putamen and brain regions that play key integrative roles in eye-blinking and other behavior. These findings support eye-blinking as a non-invasive cross-species indicator of dopaminergic subtype activation that can be used to enhance our understanding of dopamine-related dysfunction in neuropsychiatric disorders.

01 Jun 2025·PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR

Monoamine receptors targeted by methamphetamine differentially modulate basal and fentanyl-depressed respiration in mice

Article

Author: Walentiny, D Matthew ; Elder, Harrison J ; Beardsley, Patrick M

RATIONALE:

Fentanyl remains the primary cause of fatal overdoses, and its co-use with methamphetamine is a growing concern. Our lab previously demonstrated that racemic methamphetamine could have either respiratory stimulant or depressant effects depending on dose and separately determined by its enantiomers, dextromethamphetamine, and levomethamphetamine, respectively. Enantiomeric separation of methamphetamine's stimulant and depressant effects indicates that differences in their pharmacology might be exploited to develop novel respiratory stimulants. It is presently unknown which of methamphetamine's monoamine receptor mechanisms mediate these respiratory effects. Thus, systematic evaluation of monoamine receptor-selective agents may identify treatment targets for OIRD.

METHODS:

Six selective agonists at monoamine receptors involved in methamphetamine's activity [phenylephrine (PNE; α₁), clonidine (CLON; α₂), SKF-82958 (SKF; D₁), quinpirole (QPR; D₂-like), 8-OH-DPAT (8-OH; 5HT_1A), and DOI (5HT₂)] were tested in adult male mice to determine their effects on basal and fentanyl-depressed minute volume (MVb; i.e., respiratory frequency x tidal volume) using whole-body plethysmography. Agonists were initially tested at three behaviorally active doses for their effects on basal MVb. Agonists that stimulated respiration or did not decrease respiration were then tested in combination with fentanyl.

RESULTS:

The α₁ and D₁ agonists PNE and SKF dose-dependently increased basal MVb while the α₂ and D₂-like agonists CLON and QPR depressed basal MVb. Neither serotonin receptor agonist significantly altered basal MVb. Under fentanyl-depressed conditions, SKF produced transient but significant increases in MVb, while PNE more persistently elevated it. Interestingly, DOI transiently elevated depressed MVb, while 8-OH further exacerbated OIRD.

CONCLUSIONS:

Selective activation of monoamine receptors alters basal respiration and OIRD, with D₁ and α₁ receptors representing potential targets as respiratory stimulants, whereas α₂, D₂-like, and 5HT_1A receptors may mediate the exacerbation of OIRD by methamphetamine.

01 Apr 2025·PSYCHOPHARMACOLOGY

D1 dopamine / mu opioid receptor interactions in operant conditioning assays of pain-depressed responding and drug-induced rate suppression, and a conditioned place preference procedure: assessment of therapeutic index in male Sprague Dawley rats

Article

Author: LaCourse, Hannah ; Falstad, April ; Asmus, Francesca ; King, Tamara ; Giuvelis, Denise ; Harrington, Kylee ; Bennett, Lily ; Davis, Ravin ; Stevenson, Glenn W ; Smith, Meghan

RATIONALE AND OBJECTIVES:

In vivo receptor interactions vary as a function of behavioral endpoint, with key differences between reflexive and non-reflexive measures that assess the motivational aspects of pain and pain relief. There have been no assessments of D₁ dopamine agonist / mu opioid receptor (MOR) agonist interactions in non-reflexive behavioral measures of pain. We examined the hypothesis that D₁/MOR mixtures show enhanced effectiveness in blocking pain depressed behaviors while showing decreased side effects such as sedation and drug reward.

METHODS:

SKF82958 and methadone were used as selective/high efficacy D₁ and mu agonists, respectively. An FR10 operant schedule was utilized in the presence and absence of a lactic acid inflammatory pain-like manipulation, to measure antinociceptive and operant-rate-suppressing effects, respectively. Rewarding properties of the drug combinations were determined using a conditioned place preference procedure.

RESULTS:

Methadone alone, but not SKF82958 alone, produced dose-dependent restoration of pain-depressed responding. Both SKF82958 and methadone produced dose-dependent response rate suppression. Three fixed proportion mixtures, based on the relative potencies of the drugs in the rate suppression assay, produced dose-dependent antinociception and sedation. Isobolographic analysis indicated that the 0.17:1 mixture produced supra-additive antinociception and additive sedation. The 0.055:1 mixture produced additive antinociception with sub-additive sedation, and the 0.018:1 mixture had the highest therapeutic index (TI) relative to other mixtures and drugs alone. The antinociceptive doses and component doses for the 0.018:1 mixture did not produce conditioned place preference.

CONCLUSIONS:

These results suggest that D₁-selective dopamine agonists may have utility as candidate opioid-sparing analgesics.

100 Deals associated with SKF-82958

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