Synthesis and Structure−Affinity−Activity Relationships of Novel Benzofuran Derivatives as MT₂ Melatonin Receptor Selective Ligands

Abstract

A series of N-(2-phenylbenzofuran-3-yl) ethyl amide and N-(2-arylalkylbenzofuran-3-yl) ethyl amide derivatives were synthesized and evaluated as melatonin receptor ligands. The affinity of each compound for the two MT(1) and MT(2) melatonin receptor subtypes was determined by binding studies using 2-[(125)I]iodomelatonin on human embryonic kidney cell line HEK293 membrane homogenates. The intrinsic activity of the most interesting compounds was evaluated on the [(35)S]GTPgammaS binding assay. Introduction of a 2-phenyl substituent in the C-2 benzofuran position leads to an agonist compound, 10q, which binds more strongly than melatonin itself to both MT(1) and MT(2) subtypes. On the other hand, a 2-benzyl group in the same position allows MT(2) antagonist selective ligands to be obtained. The MT(2) selectivity and antagonist potency can be modulated with suitable modifications on the N-acyl and benzyl substituents, and the most selective compounds 10c and 19 show affinity ratios of 123 and 192, respectively, and bind to the MT(2) subtype similarly to melatonin itself (0.1 nM). Nevertheless, 10c acts as an MT(1) and MT(2) antagonist, whereas 19 is a partial agonist.

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

“…Binding studies performed on the cloned receptors confirmed the MT 2 selectivity. Other publications (Wallez et al, 2002;Audinot et al, 2003;Yous et al, 2003) reported selective MT 2 ligands with a benzyl substituent in the 2-position of benzofuran bioisosters (S 24014) or a phenyl substituent in the 3-position of tetrahydronaphthalenic (S 28407) or naphthalenic (S 24773) bioisosteres. 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.…”

New substrate analogues of human serotonin N‐acetyltransferase produce in situ specific and potent inhibitors

“…Indeed, our data suggest that they are acetyl-CoA binding, as well as substratebinding site competitive inhibitors because they occupy the cosubstrate site. As these compounds are broad analogues of melatonin [16][17][18][19][20][21][22][23][24][25], we report their affinities for the MT 1 and/or MT 2 receptors.…”

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

“…The effect of the ureido group is consistent with data from other series, in which ureido agonists and antagonists are usually 5-10-fold less potent than the corresponding amide analogues. [22][23][24] Compound 3 retains discrete binding affinity, even if published data for other ester derivatives would lead one to expect a remarkable loss of binding affinity, relative to their amide analogues. In fact, ethyl 2-(5-methoxyindol-3-yl)acetate [25] and ethyl 2-(7-methoxynaphthalen-1-yl)acetate [26] showed about 1000-fold lower affinity than MLT or agomelatine (N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide), respectively, toward receptors expressed on native tissues.…”

“…If E max is between 30 and 70 % that of MLT (0.3 < IA r < 0.7) the compound is considered a partial agonist, whereas if E max is lower than 30 % (IA r < 0.3) the compound is considered an antagonist. [22] …”