Delving into the Latest Updates on 5-HT1A receptor agonists(Neurolixis) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Compound 6(Neurolixis)

Target

5-HT1A receptor

Action

agonists

Mechanism

5-HT1A receptor agonists(Serotonin 1a (5-HT1a) receptor agonists)

Therapeutic Areas

Nervous System DiseasesEndocrinology and Metabolic Disease

Active Indication

Depressive DisorderParkinson Disease

Inactive Indication-

Originator Organization

Uniwersytet Jagiellonski Collegium Medicum

Neurolixis, Inc.

Active Organization

Neurolixis, Inc.

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC23H24ClF2N3O2

InChIKeyKOWBAFDEMIDBCY-UHFFFAOYSA-N

CAS Registry2170405-36-2

Norepinephrine and Dopamine (DA) are critical brain amines in Attention Deficit Hyperactivity Disorder (ADHD), with treatments targeting their neuroreceptors often causing adverse effects, particularly in the motor system through DA receptors. Our earlier study suggested that chronic treatment with a 5-HT1A receptor agonist or a 5-HT2A receptor antagonist in juvenile spontaneously hypertensive rats (SHRs) may improve ADHD-like symptoms by potentially modulating DA receptors. This study investigated the long-term impacts of these serotonergic receptor manipulations on ADHD behavior.

Methods::

Male SHRs (15 days old) received either ipsapirone (a 5-HT1A agonist) or MDL100907 (a 5-HT2A antagonist) from postnatal day (PND) 15 to 42, in parallel with similarly aged Wistar Kyoto rats (WKY). After eight weeks of undisturbed observation, we assessed hyperlocomotor activity, anxiety, and impulsivity. On PND 122, rats were sacrificed, and the striatum and prefrontal cortex (PFC) were analyzed for DA-D1, DA-D2, 5-HT1A, and 5-HT2A receptor proteins and DA levels.

Results::

The results showed that both treatments had lasting positive effects on ADHD behaviors, linked to increased 5-HT1A and 5-HT2A receptors in the PFC and striatum. Ipsapirone (5-HT1A agonist) did not alter DA receptor expression but reduced DA levels, while the 5-HT2A antagonist reduced DA-D2 and increased DA-D1 expression, with enhanced DA content levels. In the striatum, both treatments increased DA-D2 and reduced DA-D1 receptors, but the 5-HT1A agonist lowered DA content.

Discussion::

Striatal DA-D2 dysregulation appears to contribute to hyperlocomotor activity, while attentional impairments are associated with enhanced striatal DA-D2 receptor expression. Enhancing 5-HT activity either through 5-HT2A antagonists or 5-HT1A agonists effectively alleviates core ADHD symptoms in SHRs, likely by indirectly modulating DA signaling. These serotonergic agents may influence DA pathway activity via cortical mechanisms, providing therapeutic benefits without the long-term adverse effects typically associated with direct DA receptor blockade.

Conclusion::

These findings suggest that dysregulation of 5-HT1A and DA-D2 receptors may contribute to ADHD, and monotherapy with either a 5-HT1A receptor stimulator or a 5-HT2A receptor inhibitor can effectively alleviate core ADHD symptoms long-term, likely through indirect DA system modulation.

05 Jan 2026·Sexual Medicine Reviews

On-demand testosterone for the treatment of female sexual dysfunction: a systematic review

Review

Author: Pace, Keiran ; Fleshner, Neil E ; Mansouri, Sara ; Kaushal, Sanchit ; Cockburn, Jessica G ; Yin, Leyi B ; Bernardino, Rui M

Abstract:

Introduction:

Female sexual dysfunction is common, distressing, and notoriously difficult to treat. In the last two decades, short-course (“on-demand”) testosterone (T) regimens—delivered sublingually, intranasally, inhaled, topically, or intramuscularly—have been explored as rapid-acting prn enhancers of female libido. The objective of this study is to quantify efficacy, safety, and pharmacokinetics (PK) of short-term T therapy (prn) in women with sexual dysfunction.

Methods:

PRISMA 2020 guidelines for systematic reviews were followed. Twelve RCTs and five PK studies (n = 940) were identified via Embase/MEDLINE/Web of Science (inception–March 2025). Outcomes included desire/arousal scores, satisfying sexual events (SSE), pharmacokinetics, and adverse events. Risk of bias was assessed using the Cochrane risk-of-bias tool.

Results:

Although absolute serum T excursions differ widely across formulations, most achieve supra-physiological free-T peaks within 15 min and return to baseline within 2-6 h. There is mixed evidence that this window coincides with maximal central arousal effects. However, when combined with phosphodiesterase-5 or 5-HT1A agonists, there tends to be improved genital vasocongestion and sexual satisfaction. Adverse events were mild but tended to be common.

Conclusions:

Short-term T therapy combined with phosphodiesterase-5 inhibitors or 5-HT1A agonists may be benefit select subgroups of women with sexual dysfunction with a favorable short-term safety, however, sample sizes remain small and further research is required.Registration: This study was registered in PROSPERO: CRD42024615106.

12 Jun 2025·ACS Medicinal Chemistry Letters

Novel Substituted Lactams as 5-HT1A Agonists for Treating Neuropsychiatric Diseases

Author: Sabnis, Ram W.

Provided herein are novel substituted lactams as 5-HT1A agonists, pharmaceutical compositions, use of such compounds in treating neuropsychiatric diseases and processes for preparing such compounds.

100 Deals associated with 5-HT1A receptor agonists(Neurolixis)

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