Serotonin receptor-targeting compounds and methods
This invention relates to, in part, compositions and methods that are useful for, inter alia, the treatment of various diseases, including those linked to binding at a serotonin receptor. The compositions include chiral tetrahydronaphthalen-2-amine derivatives. Accordingly, the present invention provides for compositions and methods that agonize or antagonize one or more serotonin receptors and which find Use in the treatment of various neuropsychiatric diseases or disorders including, without limitation, autism spectrum disorder (ASD) or associated symptoms.
1. A pharmaceutical composition, comprising a therapeutically effective amount of an at least about 90% pure (S)-enantiomer dual partial agonist at the serotonin 5-HT 7 and 5-HT 1A receptors, the dual partial agonist having the structure of Formula (I):
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
each of R 1 and R 2 is independently hydrogen or alkyl;
R 3 and R 7 are each independently hydrogen, chloro, fluoro, or amino;
R 5 is hydrogen or fluoro;
each of R 4 and R 6 is independently hydrogen, chloro, fluoro, alkoxy, or trifluoromethyl;
each of R 8 , R 9 , and R 10 is independently hydrogen or alkoxy, but if R 10 is alkoxy at least one of R 8 and R 9 is also alkoxy;
such that at least one of R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is not hydrogen, or wherein R 4 and R 5 and R 6 and R 7 are joined to form an unsubstituted anthracene ring;
and a pharmaceutically acceptable excipient or carrier.
2. The pharmaceutical composition of claim 1 , wherein the dual partial agonist binds to serotonin 5-HT 7 receptor and/or the 5-HT 1A receptor with a binding affinity (K i ) of less than about 100 nM, or less than about 50 nM, or less than about 25 nM, or less than about 20 nM, or less than about 10 nM, or less than about 5 nM, or less than about 2 nM, or less than about 1 nM.
3. The pharmaceutical composition of claim 1 , wherein the dual partial agonist does not bind one or more of the serotonin 5-HT 2A and 5-HT 2C receptors at physiologically-relevant levels.
4. The pharmaceutical composition of claim 1 , wherein the dual partial agonist binds one or more of the serotonin 5-HT 7 and 5-HT 1A receptors with at least about 10-fold, or at least about 20-fold, or at least about 30-fold, or at least about 40-fold, or at least about 50-fold, or at least about 75-fold, or at least about 100-fold higher affinity than one or more of the serotonin 5-HT 2A and 5-HT 2C receptors.
5. The pharmaceutical composition of claim 1 , wherein the dual partial agonist binds one or more of the serotonin 5-HT 7 and 5-HT 1A receptors with an at least about 10-fold, or at least about 20-fold, or at least about 30-fold, or at least about 40-fold, or at least about 50-fold, or at least about 75-fold, or at least about 100-fold higher affinity than a corresponding enantiomer.
6. The pharmaceutical composition of claim 1 , wherein the dual partial agonist does not bind one or more of the histamine H1 receptor, dopamine D2, and adrenergic α 1A and α 1B receptors at physiologically-relevant levels.
7. The pharmaceutical composition of claim 1 , wherein at least one of R 3 , R 4 , R 5 , R 6 , and R 7 is fluoro.
8. The pharmaceutical composition of claim 1 , wherein only R 3 is a substituent other than H.
9. The pharmaceutical composition of claim 8 , wherein R 3 is chloro or fluoro.
10. The pharmaceutical composition of claim 1 , wherein at least one of R 8 , R 9 , and R 10 is methoxy.
11. The pharmaceutical composition of claim 1 , wherein the dual partial agonist is:
12. A compound having the structure of one of:
13. A method of treating or preventing a neuropsychiatric disease or disorder, comprising administering an effective amount of a composition of claim 1 to a patient in need thereof.
14. The method of claim 13 , wherein the neuropsychiatric disease or disorder is one or more of autism, anxiety, depression, obsessive-compulsive disorders, schizophrenia, suicide, migraine, emesis, alcoholism and neurodegenerative disorders.
15. The method of claim 13 , wherein the neuropsychiatric disease or disorder is selected from autism spectrum disorder (ASD); Asperger syndrome, Fragile X syndrome (FXS), Prader-Willi syndrome, Rett syndrome, Tourette syndrome, attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder, psychotic disorders, psychostimulant addiction and generalized anxiety.
16. The method of claim 13 , wherein the treatment comprises a reduction in the frequency of one or more of stereotypy, self-injurious behaviors, compulsions, and tics.
17. A method of treating autism spectrum disorder (ASD), comprising administering an effective amount of a composition of claim 1 to a patient in need thereof.
18. A method of treating stereotypy, comprising administering an effective amount of a composition of claim 1 to a patient in need thereof.
19. A method of selectively modulating serotonin 5-HT 7 and 5-HT 1A receptors, comprising contacting a cell with a composition of claim 1 , wherein the modulation is partial antagonism.