A novel aminotetralin-type serotonin (5-HT) 2C receptor-specific agonist and 5-HT2A competitive antagonist/5-HT2B inverse agonist with preclinical efficacy for psychoses

Abstract

Development of 5-HT2C agonists for treatment of neuropsychiatric disorders, including psychoses, substance abuse, and obesity, has been fraught with difficulties, because the vast majority of reported 5-HT2C selective agonists also activate 5-HT2A and/or 5-HT2B receptors, potentially causing hallucinations and/or cardiac valvulopathy. Herein is described a novel, potent, and efficacious human 5-HT2C receptor agonist, (-)-trans-(2S,4R)-4-(3'[meta]-bromophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (-)-MBP), that is a competitive antagonist and inverse agonist at human 5-HT2A and 5-HT2B receptors, respectively. (-)-MBP has efficacy comparable to the prototypical second-generation antipsychotic drug clozapine in three C57Bl/6 mouse models of drug-induced psychoses: the head-twitch response elicited by [2,5]-dimethoxy-4-iodoamphetamine; hyperlocomotion induced by MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (dizocilpine maleate)]; and hyperlocomotion induced by amphetamine. (-)-MBP, however, does not alter locomotion when administered alone, distinguishing it from clozapine, which suppresses locomotion. Finally, consumption of highly palatable food by mice was not increased by (-)-MBP at a dose that produced at least 50% maximal efficacy in the psychoses models. Compared with (-)-MBP, the enantiomer (+)-MBP was much less active across in vitro affinity and functional assays using mouse and human receptors and also translated in vivo with comparably lower potency and efficacy. Results indicate a 5-HT2C receptor-specific agonist, such as (-)-MBP, may be pharmacotherapeutic for psychoses, without liability for obesity, hallucinations, heart disease, sedation, or motoric disorders.

Fig. 1.

Structures of (+)-MBP and (−)-MBP.

Fig. 2.

Representative functional responses of (−)-MBP at human 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors compared with 5-HT.

Fig. 3.

(A) Representative competitive antagonism results of (−)-MBP at human 5-HT_2A receptors. (B) Representative inverse agonist results of (−)-MBP at human 5-HT_2B receptors.

Fig. 4.

(A) Both enantiomers of (−)-MBP dose-dependently attenuated the DOI-elicited HTR. (−)-MBP was more potent and efficacious than (+)-MBP, consistent with in vitro pharmacology data. Clozapine (CLOZ) also dose-dependently blocked the DOI-elicited HTR. Each data point represents the mean (± S.E.M.) of 5 to 7 subjects. All drug groups are significantly different from the DOI-only group (vehicle). (B) Pretreatment with (−)-MBP did not affect locomotion, but CLOZ and (+)-MBP significantly decreased locomotion relative to DOI (1 mg/kg). CLOZ also reduced locomotion compared with the group treated with vehicle (Veh) only; numbers on the x-axis refer to mg/kg dose. Bar graphs of locomotion (mean ± S.E.M.) are from representative groups shown in A. *Significantly different from DOI. ^#Significantly different from vehicle.

Fig. 5.

(−)-MBP dose-dependently attenuated MK-801-elicited hyperactivity, similar to clozapine (CLOZ). Effects are shown for the total 60-minute session (bar graphs), and numbers on the x-axis refer to dose in mg/kg. Bar graphs represent the mean (± S.E.M.) of 6 (CLOZ groups) to 10 subjects. *Significantly different from MK-801 alone. Inset: Effects are plotted in 1-minute bins for the primary comparisons. Error bars in inset are excluded for clarity.

Fig. 6.

Time course analysis of (−)-MBP (10 mg/kg). (−)-MBP administered 10 or 60 minutes before MK-801 significantly reduced MK-801-elicited hyperactivity. Effects are shown for the total 60-minute session (bar graphs). Bar graphs represent the mean (± S.E.M.) of 11 (vehicle) and 6 (for each of the remaining groups) subjects. *Significantly lower activity relative to MK-801 alone. Inset: Effects are plotted in 1-minute bins for the primary comparisons. Error bars in inset are excluded for clarity.

Fig. 7.

(−)-MBP attenuated amphetamine (AMP)-elicited increases in locomotion, similar to clozapine (CLOZ) but with less potency (groups right of dashed line). Note, however, that CLOZ (1 mg/kg) alone significantly decreased locomotion, but (−)-MBP (10 mg/kg) alone did not alter locomotion, relative to vehicle (Veh) (groups left of dashed line). Effects are shown for the total 60-minute session (bar graphs), and numbers on the x-axis refer to dose in mg/kg. Bar graphs represent the mean (± S.E.M.) of six (CLOZ groups) to nine subjects. *Combination of CLOZ or (−)-MBP with AMP was significantly lower relative to AMP alone. ^#Significantly different from vehicle group. Inset: Effects are plotted in 1-minute bins for the primary comparisons. Error bars in inset are excluded for clarity.

Fig. 8.

Both (+) and (−)-MBP decreased consumption of “Crunchies,” a highly palatable treat, in non-food-deprived mice. Bar graphs represent the mean (± S.E.M.) of eight subjects. Both doses of (−)-MBP (outlined, red bars), and the highest dose of the (+)-MBP (gray bars) decreased consumption. *Significantly lower levels of consumption relative to vehicle administration.