title: Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy.
abstract: BACKGROUND
  The rhythmic opening and tightly closing of cardiac valve leaflets are cardiac cyclic events imposing to blood a unidirectional course along the vascular tree. Drugs with 5-HT2B agonism properties can seriously compromise this biological function critical for hemodynamic efficiency as their intrinsic pro-fibrotic effects can, with time, make valvular coaptation blood regurgitant.
  Cardiac valve anatomy, physiology and pathology as well as 5-HT2B receptor properties (coupling, effects mediated, biased agonism) are briefly exposed. Approaches to unveil 5-HT2B receptor liability of drug candidates are detailed. In silico computational models can rapidly probe molecules for chemical signatures associated with 5-HT2B receptor affinity. In vitro radioligand competition assays allow quantifying receptor binding capacity (Ki, IC50), the pharmacological nature (agonism, antagonism) of which can be ascertained from cytosolic second messenger (inositol phosphates, Ca(++), MAPK2) changes. Potencies calculated from the latter data may exhibit variability as they are dependent upon the readout measured and the experimental conditions (e.g., receptor density level of cell material expressing human 5-HT2B receptors). The in vivo valvulopathy effects of 5-HT2B receptor agonists can be assessed by echocardiographic measurements and valve histology in rats chronically treated with the candidate drug. Finally, safety margins derived from from nonclinical and clinical data are evaluated in terms of the readout, usefulness and scientific reliability.
  
  
  CONCLUSIONS
  The Safety Pharmacology toolbox for detecting possible 5-HT2B receptor agonism liabilities of candidate drugs requires meticulous optimization and validation of all its (in silico, in vitro and in vivo) components to perfect its human predictability power. In particular, since 5-HT2B receptor agonism is biased in nature, the most predictive readout(s) of valvular liability should be identified and prioritized in keeping with best scientific practice teachings.
authors.affiliation: 54 Rue de la Glacière, 75013 Paris, France. Electronic address: iciliocavero@aol.com.
authors.forename: Icilio
authors.initials: I
authors.lastname: Cavero
authors.affiliation: Sanofi, Preclinical Safety, Pharmacology, 13 quai Jules Guesde, 94403 Vitry sur Seine, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Guillon
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000592:standards; D004452:Echocardiography; D006349:Heart Valve Diseases / Q000139:chemically induced* / Q000378:metabolism*; D006801:Humans; D051381:Rats; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000009:adverse effects*
chemical_list: D044403:Receptor, Serotonin, 5-HT2B; D058826:Serotonin 5-HT2 Receptor Agonists
keywords: 5-HT(2(A,B,C,)) receptor families; Assays for 5-HT(2B) receptor agonism liability; Biased agonism; Cardiac valve leaflets; Cardiac valvulopathy; Cell-based functional assays; Criteria to progress compounds with 5-HT(2B) receptor agonism to human evaluation; Ligand binding assays; Pharmacodynamic assays for cardiac valve lesions; Safety Pharmacology