Table 1.

Examples of orthosteric agonists and allosteric modulators of the calcium-sensing receptor[13-15]

Ligand type	Class and examples	Reported effects on inflammation	Reported effects on cancer	Ref.
Orthosteric agonists	Inorganic divalent and trivalent cations: Zn2+ 1Ca2+; Mg2+; Gd3+	Reduces inflammation in mouse models of colitis	High Ca2+ intake: Associated low risk for CRC	[16-18]
		Intake is correlated with reduced inflammation
	Polyamines: Spermine spermidine, putrescine	Increase airway inflammation and hyperresponsiveness	Reduce pancreatic cancer growth in mice	[5,19]
	Aminoglycoside antibiotics: Neomycin, gentamycin, tobramycin	-	-
	Basic polypeptides: poly-l-arginine, 1poly-l-lysine, and amyloid β-peptides	Induces airway inflammation	-	[5,20]
		Reduces inflammation in mouse models of colitis
Combined orthosteric and allosteric modulators	D-amino-acid polypeptides: Etelcalcetide	-	-
	L-amino acids: Phenylalanine, tryptophan	-	-
	Glutamyl dipeptides: 1γ-Glu-Val, 1γ-Glu-Cys	Reduces inflammation in mouse models of colitis	-	[21]
Allosteric modulators (calcimimetics and calcilytics)	Small molecule calcimimetics: Sensipar (1Cinacalcet HCl), NPS-R568, GSK3004774	Increases airway hyperresponsiveness	Treatment of parathyroid tumours	[5,22-24]
			Inhibits neuroblastoma tumour growth
			Reduces hypercalcaemia of malignancy
	Small molecule calcilytics: 1NPS-2143, Calhex, Ronacalaret, AXT-914	Reduces pulmonary inflammation and airway hyperresponsiveness in rodents	-	[5,25,26]

¹Indicates the compounds for which the in vivo effects were reported. While many of these modulators have been reported to have in vitro effects on (cancer) cell lines, evidence of their in vivo activity has remained scarce. The table summarises their known (putatively) CaSR-mediated direct effects on inflammation and cancer in humans or animals. CRC: Colorectal cancer.