2. Academic Validation
  3. Comparative Pharmacological Profiling of Psychotherapeutic Drugs Reveals a Functional Taxonomy Based on Direct Inhibition of Smooth Muscle Excitability

Comparative Pharmacological Profiling of Psychotherapeutic Drugs Reveals a Functional Taxonomy Based on Direct Inhibition of Smooth Muscle Excitability

  • Pharmaceuticals (Basel). 2026 Apr 21;19(4):645. doi: 10.3390/ph19040645.
María Jesús Castrillejo 1,  Alfonso Velasco 2 3,  Juan F Mielgo-Ayuso 4 5,  Jesús Pérez 6,  Manuel Garrosa 3 7 8,  Carlos Alberto Rodríguez-Arias 3 8 9,  Diego Fernández-Lázaro 8 10 11
Affiliations

Affiliations

  • 1 Department of Cell Biology, Genetics, Histology and Pharmacology, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain.
  • 2 Department of Cell Biology, Genetics, Histology and Pharmacology, Faculty of Medicine, Institute of Neurosciences of Castile and Leon (INCYL), University of Valladolid, 47005 Valladolid, Spain.
  • 3 Degeneration and Regeneration Laboratory, Institute of Neurosciences of Castile and Leon (INCYL), University of Valladolid, 47005 Valladolid, Spain.
  • 4 Faculty of Health Sciences, University of Burgos (UBU), 09001 Burgos, Spain.
  • 5 Advanced Research in Integrative Physiology for Life Research Group (IAFIV), University of Burgos (UBU), 09001 Burgos, Spain.
  • 6 Department of Medicine, Faculty of Medicine, Institute of Biomedical Research (IBSAL), University of Salamanca, 37007 Salamanca, Spain.
  • 7 Area of Histology, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain.
  • 8 Neurobiology Research Group, University of Valladolid, 47005 Valladolid, Spain.
  • 9 Neurosurgery Department, Hospital Clínico Universitario de Valladolid, Institute of Neurosciences of Castile and Leon (INCYL), 47003 Valladolid, Spain.
  • 10 Area of Histology, Faculty of Health Sciences, University of Valladolid, 42004 Soria, Spain.
  • 11 Biomedical Research Institute of León (IBIOLEÓN), University Hospital Complex of León, 24071 León, Spain.
PMID: 42075900 DOI: 10.3390/ph19040645
Abstract

Background: Autonomic side effects are a major determinant of tolerability for many psychotherapeutic drugs. While often attributed to receptor-mediated mechanisms, the potential contribution of direct modulation of smooth muscle excitability remains poorly characterized at a comparative pharmacological level. Methods: A systematic comparative pharmacological profiling of a broad panel of psychotherapeutic drugs (antidepressants, antipsychotics, and anxiolytics) was conducted using a standardized ex vivo model. Potassium chloride (KCl, 105 mM) was used to induce depolarization-dependent contraction in three isolated smooth muscle preparations (rat uterus, rat vas deferens, and guinea-pig ileum). Inhibitory potency (IC50), dose-dependency, and tissue consistency were integrated to define functional inhibitory profiles. Results: Psychotherapeutic drugs exhibited marked heterogeneity in their ability to inhibit K+-induced smooth muscle contraction. Integrative analysis stratified compounds into four distinct functional profiles: (i) High Inhibitory Liability (e.g., nortriptyline, paroxetine), characterized by low micromolar IC50 values and dose-dependent inhibition across multiple tissues; (ii) Non-Selective Inhibition (e.g., flunarizine, cinnarizine), showing consistent but dose-independent inhibition; (iii) Tissue-Dependent Inhibition (e.g., risperidone, reboxetine); and (iv) Minimal Inhibition (e.g., moclobemide). Agents classified within the High Inhibitory Liability profile correspond to drugs known to carry a higher clinical burden of autonomic adverse effects. Conclusions: This study reveals a previously underrecognized pharmacodynamic dimension of psychotherapeutic drugs and establishes a comparative functional taxonomy based on their direct, non-receptor-mediated inhibition of smooth muscle excitability. The identified profiles provide a mechanism-informed framework for contextualizing autonomic side-effect liability and may support improved safety evaluation in psychotherapeutic drug development.

Keywords

K+-induced depolarization; autonomic side-effect liability; ex vivo assay; functional pharmacological profiling; psychotherapeutic drugs; smooth muscle excitability.

Figures
Products