A critical re-evaluation of the slope factor of the operational model of agonism: When to exponentiate operational efficacy.

Agonist efficacy denoting the "strength" of agonist action is a cornerstone in the proper assessment of agonist selectivity and signalling bias. The simulation models are very accurate but complex and hard to fit experimental data. The parsimonious operational model of agonism (OMA) has become successful in the determination of agonist efficacies and ranking them.

Modulation of Muscarinic Signalling in the Central Nervous System by Steroid Hormones and Neurosteroids.

Muscarinic acetylcholine receptors expressed in the central nervous system mediate various functions, including cognition, memory, or reward. Therefore, muscarinic receptors represent potential pharmacological targets for various diseases and conditions, such as Alzheimer's disease, schizophrenia, addiction, epilepsy, or depression. Muscarinic receptors are allosterically modulated by neurosteroids and steroid hormones at physiologically relevant concentrations.

Insights into the operational model of agonism of receptor dimers.

Introduction: Accurate ranking of efficacies and potencies of agonists is essential in the discovery of new selective agonists. For the purpose of system-independent ranking of agonists, the operational model of agonism (OMA) has become a standard. Many receptors function as oligomers which makes functional responses more complex, requiring an extension of the original OMA.

Allosteric Modulation of Muscarinic Receptors by Cholesterol, Neurosteroids and Neuroactive Steroids.

Muscarinic acetylcholine receptors are membrane receptors involved in many physiological processes. Malfunction of muscarinic signaling is a cause of various internal diseases, as well as psychiatric and neurologic conditions. Cholesterol, neurosteroids, neuroactive steroids, and steroid hormones are molecules of steroid origin that, besides having well-known genomic effects, also modulate membrane proteins including muscarinic acetylcholine receptors.

Novel D/5-HT receptor modulators related to cariprazine with potential implication to schizophrenia treatment.

Schizophrenia is a serious mental disorder without a fully understood pathomechanism, but which involves dysregulation of neurotransmitters and their receptors. The best option for the management of schizophrenia comprises so-called multi-target ligands, similar to the third generation of neuroleptics. Dopamine type 2 receptors (DRs) are the main target in the treatment of schizophrenia, in particular for mitigation of the positive symptoms.