Abstract
Melanin-concentrating hormone (MCH) is a cyclic peptide produced in the lateral hypothalamus. It has been implicated in a number of physiological processes including feeding behavior, energy balance, and the regulation of emotional states. Here, we report in vitro and in vivo profiles of ATC0065 [N2-[cis-4-({2-[4-bromo-2-(trifluoromethoxy)phenyl]ethyl}amino)cyclohexyl]-N4, N4-dimethylquinazoline-2,4-diamine dihydrochloride] and ATC0175 [N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorobenzamide hydrochloride], newly synthesized MCH receptor 1 (MCHR1) antagonists. Both ATC0065 and ATC0175 had high affinities for human MCHR1 with IC50 values of 15.7 ± 1.95 and 7.23 ± 0.59 nM, respectively. Both ATC0065 (IC50 = 21.4 ± 1.57 nM) and ATC0175 (IC50 = 13.5 ± 0.78 nM) showed potent antagonist activities at MCHR1, as assessed by MCH-increased guanosine 5′-O-(3-[35S]thio)phosphate ([35S]GTPγS) binding to human MCHR1. Oral administration of ATC0065 (3–30 mg/kg) or ATC0175 (1–10 mg/kg) significantly reduced immobility time in the forced swimming test in rats, indicating antidepressant-like effects. Both ATC0065 and ATC0175 significantly reversed swim stress-induced anxiety in the elevated plus-maze test in rats and stress-induced hyperthermia in mice. ATC0175 significantly increased social interaction between unfamiliar rats and reduced separation-induced vocalizations in guinea pig pups, indicating anxiolytic potential. In contrast, ATC0065 and ATC0175 did not affect spontaneous locomotor activity or rotarod performance in rats. These findings indicate that ATC0065 and ATC0175 are potent and orally active MCHR1 antagonists with anxiolytic and antidepressant activity in rodents.
Footnotes
-
doi:10.1124/jpet.104.081711.
-
ABBREVIATIONS: MCH, melanin-concentrating hormone; MCHR, MCH receptor; ACTH, adrenocorticotropic hormone; CRF, corticotropin-releasing factor; HPA, hypothalamus-pituitary-adrenal; ATC0065, N2-[cis-4-({2-[4-bromo-2-(trifluoromethoxy)phenyl]ethyl}amino)cyclohexyl]-N4, N4-dimethylquinazoline-2,4-diamine dihydrochloride; ATC0175, N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorobenzamide hydrochloride; T-226296, (–)-N-[6-(dimethylamino)-methyl]-5,6,7,8-tetrahydro-2-naphthalenyl]-4′-fluoro[1,1′-biphenyl]-4-carboxamide; SNAP-7941, (+)-methyl (4S)-3-{[(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)amino]carbonyl}-4-(3,4-difluoropheny)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetra-hydro-5-pyrimidinecarboxylate hydrochloride; 8-OH-DPAT, 8-hydroxy-2-dipropylaminotetralin; LSD, lyserigic acid diethylamide; NAN-190, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine hydrobromide; [35S]GTPγS, 5′-O-(3-[35S]thio)phosphate; CHO, Chinese hamster ovary; 5-HT, 5-hydroxytryptamine; SSRI, selective serotonin reuptake inhibitor.
- Received December 3, 2004.
- Accepted January 25, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|