Methods for treating depressive symptoms
The present application relates methods for treating a depressive symptom comprising administering an effective amount of a μ opioid receptor agonist or a pharmaceutically acceptable salt thereof to a subject in need thereof. Non-limiting examples of such agonist include the compounds of Formulas I, II, III, and IV, as well as the compounds of Table A.
1. A method of treating a depressive symptom in a subject comprising administering to the subject a compound of Formula IV:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, aryl, cycloalkyl, heterocyclyl, benzyl, hydroxyalkyl, or alkoxyalkyl;
R 1a is H or methyl;
R 2 is H, hydroxyl, or methoxy; and
R 3 and R 4 are each methyl, or alternatively, R 3 and R 4 , together with the carbon atoms to which they are attached, form a 6-membered unsubstituted carbocyclic ring;
wherein the depressive symptom is selected from the group consisting of depressed mood, loss of pleasure, loss of appetite, sleep disturbance, psychomotor changes, fatigue, post-partum depression, a depressive symptom associated with a mental condition, acute stress disorder, an adjustment disorder with depressed mood, Asperger syndrome, attention deficit, bereavement, bipolar I disorder, bipolar II disorder, borderline and personality disorder, cyclothymia, dysthymia, depression, Dysthymic disorder, hyperactivity disorder, impulse control disorder, mixed mania, obsessive-compulsive personality disorder (OCD), paranoid, post-traumatic stress disorder, seasonal affective disorder, self-injury separation, sleep disorder, substance-induced mood disorder, Tourette syndrome, tic disorder, Trichotillomania, a depressive symptom associated with an anxiety disorder, chronic depression, and recurrent depression.
2. The method according to claim 1 , wherein the compound of Formula IV is:
3. The method of claim 1 , wherein the compound is a μ opioid receptor agonist that exhibits an Emax of 5% to 45% in a GTPγS binding assay.
4. The method of claim 3 , wherein the Emax is 15% to 35% in a GTPγS binding assay.
5. The method of claim 3 , wherein said agonist has a low risk of opioid dependence, opioid addiction, and/or symptoms of opioid withdrawal.
6. The method of claim 1 , wherein the compound exhibits a maximal dopamine efflux in the nucleus accumbens of 125% to 300% over base line in a rat.
7. The method of claim 6 , wherein the compound has a maximal dopamine efflux in the nucleus accumbens of 200% to 300% over base line in a rat.
8. The method of claim 1 , wherein the compound does not attenuate thermal pain in a rodent hot plate model when administered at a dose of at least 1 mg/kg.
9. The method of claim 8 , wherein the compound does not attenuate thermal pain in a rodent hot plate model when administered at a dose of at least 3 mg/kg.
10. The method of claim 8 , wherein the compound does not attenuate thermal pain in a rodent hot plate model when administered at a dose of 10 mg/kg.
11. The method of claim 1 , wherein the subject is a human.
12. The method of claim 1 , wherein the depressive symptom is depressed mood, loss of pleasure, loss of appetite, sleep disturbance, psychomotor changes, fatigue, or post-partum depression.
13. The method of claim 1 , wherein the depressive symptom associated with a mental condition is schizoaffective disorder, or seasonal affective disorder.
14. The method of claim 1 , wherein the depressive symptom is acute stress disorder, adjustment disorders with depressed mood, Asperger syndrome, attention deficit, bereavement, bipolar I disorder, bipolar II disorder, borderline and personality disorder, cyclothymia and dysthymia, depression, Dysthymic disorder, hyperactivity disorder, impulse control disorder, mixed mania, obsessive-compulsive personality disorder (OCD), paranoid, post-traumatic stress disorder, seasonal affective disorder, self-injury separation, sleep disorder, substance-induced mood disorder, Tourette syndrome and tic disorder, or Trichotillomania.
15. The method of claim 1 , wherein the depressive symptom associated with an anxiety disorder is generalized anxiety disorder, panic, agoraphobia, acute stress, or post-traumatic stress disorder.
16. The method of claim 1 , wherein the depressive symptom is associated with chronic or recurrent depression.
17. The method of claim 14 , wherein the depression is major depressive disorder (MDD) or treatment-resistant disorder (TRD).