Synthesis and Pharmacological Analysis of High Affinity Melatonin Receptor Ligands.

Abstract

Melatonin is a hormone that is involved in a variety of physiological and pathological responses such as circadian rhythms, retinal physiology, seasonal breeding, cardiovascular regulation, anti-oxidative activity and oncogenesis. 1-7)Except anti-oxidative activity, melatonin may mediate its effect in vivo through melatonin receptors. Presently, two human melatonin receptor subtypes exist and are now defined as either the MT 1 8) (formerly known as the Mel 1a receptor) 9) and the MT 2 8) (formerly known as the Mel 1b receptor).10) The ability of melatonin or melatonin-like compounds to bind to and elicit physiological responses is dependent upon specific interactions between the ligand and receptor. The elucidation of the components of melatonergic ligands that are involved in high-affinity binding is becoming clearer. Currently, what we know is that the indole ring of melatonin is not crucial for melatonin receptor recognition. For instance, the naphthalene ring [11][12][13][14][15][16][17][18][19][20] can serve as a bioisostere of the indole nucleus of melatonin and analog 2 was reported to have equivalent affinity to melatonin for melatonin receptors in ovine pars tuberalis.11) In addition, other groups such as amidotetralin, 21) methoxychroman, 22) amido indane, 23) benzofuran, 18,24) benzothiophene 18,24) and quinoline 25) can serve as a bioisostere of the indole nucleus of melatonin. Langlois et al. reported that the addition of a 2-methoxy group (OMe) to compound 2 to form 3 results in an order of magnitude increase in receptor affinity over compound 2 (Fig. 1).12) It was postulated that the 2-OMe group binds to the accessory binding site of the receptor. Recently, we reported the synthesis and receptor binding studies of several analogs of 3 (general structure 4) with the substituents either hydrophilic or hydrophobic in nature with different sizes.16) Preliminary results show that analogs with smaller substituents in R, irrespective of their hydrophilic or hydrophobic nature, exhibit higher affinity for melatonin receptors when compared to those with larger substituents. We postulate that the close proximity of the amidoethyl side chain may be interfering with the conformation of the substituent on 2-position in 4 (Fig. 1). Thus, to determine the validity of this hypothesis, the amidoethyl group was transferred from C1 to C8 to eliminate the steric interference between the amidoethyl group and the substituent on 2-position in compound 4. The transfer should not affect the affinity of the ligands for the melatonin receptor as shown by Langlois et al. in which compound 5 (K i ϭ0.67 nM) has the same affinity for melatonin receptors in chicken brain when compared to compound 2 (K i ϭ0.54 nM) (Fig. 1). 12) After eliminating the steric interference of the amidoethyl side chain and the substituents on 2-position, we then synthesized compounds 6-10 with the substituents on 7-position of varying sizes. Results and ConclusionsChemistry The synthesis of compounds 6-10 is summarized in Fig. 2. Monobenzylation of 2,...

Microwave-Assisted Solid-Liquid Phase Alkylation of Naphthols

“…In the first three cases, the alkylations were carried out using K 2 CO 3 /acetone or Cs 2 CO 3 /MeCN systems. The yields varied in the range of 39-98% (Table 1 / Entries 1-3) [18][19][20]. 2-Naphthol (6) was benzylated using a NaOH/PhMe system and a PT catalyst.…”

Recent Advances in Melatonin Receptor Ligands

“…A series of naphthalenic melatonin receptor ligands bearing the ethylamido side chain in a position adjacent to the methoxy group, exemplified by compounds 77Ϫ78 (Figure 8), was reported by Chu et al [93]. All compounds in that series exhibited subpicomolar binding affinities to both MT 1 and MT 2 receptors expressed in CHO cells, being more potent than melatonin (MT 1 : K i ϭ 12 pM, MT 2 : K i ϭ 3 pM).…”