Indanyl piperazines as melatonergic MT2 selective agents

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

“…Following the same rationale, Spadoni et al (2001) synthesized some melatonin derivatives, 2-acylaminoalkylindoles with a substitution by a benzyl in the 1-position (compound 12), that are selective for the MT 2 receptor type. Two other selective MT 2 ligands have been reported with rigidification of the side chain of melatonin with a piperidine amide chain (GR 128107) or piperazine amide chain (compound 13) (Dubocovich et al, 1997;Mattson et al, 2003). The structure-affinity relationships for MT 2 selectivity have not been explored in these series.…”

“…Compound 13 [(R)-4-(2,3-dihydro-6-methoxy-1H-inden-1-yl)-N-ethyl-1-piperazine-carboxamidefumarate] is an agonist with selectivity for MT 2 melatonin receptors (hMT 1 /hMT 2 affinity ratio ϭ 117). Mattson et al (2003) reported that Compound 13 had lower vasoconstrictor efficacy in rat caudal arteries compared with an equimolar concentration of melatonin. Compound 13 was also found to phase advance the circadian running-wheel activity of rats when given at dose of 1 to 56 mg/kg.…”

“…However, the doses of 4P-PDOT (90 g/mouse s.c.) used in the abovementioned report (Dubocovich et al, 1998b) may have raised levels of drug in the circulation to micromolar concentrations that might have blocked both MT 1 and MT 2 melatonin receptors. Mattson et al (2003) concluded that a synthetic indanyl piperazine (compound 13) with approximately 117 times higher affinity for the MT 2 receptor (K i ϭ 200 nM for MT 1 ; 1.7 nM for MT 2 ) phase-shifted circadian activity rhythms in the rat through activation of MT 2 receptors using doses of 1 to 56 mg/kg. These doses would probably reach blood concentrations of at least 1 M, which would fully activate both the MT 1 and MT 2 receptors, thereby acting as a nonselective agonist.…”

Synthesis, Enantiomeric Resolution, and Structure–Activity Relationship Study of a Series of 10,11‐Dihydro‐5H‐Dibenzo[a,d]cycloheptene MT2 Receptor Antagonists

“…On the other hand, amide N-methylation, in compound 6, causes a significant decrease in binding affinity. While receptor binding data for N-methyl-MLT are not available, this behavior cannot be generalized to all the classes of MLT receptor ligands, particularly at the MT 2 receptor; in fact, indanylpiperazine agonists, [27] tethahydroisoquinoline antagonists, [24] and GR128107, [28] in which the amide nitrogen atom is part of a ring structure (Figure 2), retain high MT 2 binding affinities.…”

Pharmacological Characterization of a Highly Selective and Potent Partial Agonist of the MT₂ Melatonin Receptor

“…In addition, several groups have reported different MT 2 receptor-selective agonists to date [19,20,21]. However, a detailed in vitro pharmacological characterization of these MT 2 receptor agonists has not been conducted.…”