The brain consists of a plurality of neurons that communicate with each other via chemical messengers. Each neuron generates neurochemicals, referred to as neurotransmitters; and the neurotransmitters act at sites on the cellular membrane of neurons, the sites being referred to as receptors. One group of neurotransmitters, referred to as the monoamine neurotransmitters, includes serotonin, dopamine and noradrenaline.
Monoamine neurotransmitters are released into the synaptic cleft in order to stimulate postsynaptic receptor activity. The removal (or inactivation) of monoamine neurotransmitters occurs mainly by a reuptake mechanism into presynaptic terminals. By inhibiting the re-uptake an enhancement of the physiological activity of monoamine neurotransmitters occur.
Noradrenalin and serotonin re-uptake inhibitors are currently used as pharmaceuticals in anti-depressant therapy (Desipramine, Nortriptyline, and Protriptyline are inhibitors of noradrenaline-reuptake and Imipramine and Amitriptyline are mixed serotonine-reuptake and noradrenaline-reuptake inhibitors).
The pathophysiology of major affective illness is poorly understood, and several neurotransmitters have been implicated in the pathophysiology of major depression. However, several lines of preclinical and clinical evidence indicate that an enhancement of serotonin-mediated neurotransmission might underlie the therapeutic effect of the most recent and currently used drugs in anti-depressant therapy: Fluoxetine, Citalopram and Paroxetine.
Paradoxical serotonin re-uptake inhibitors inhibit the serotonin transporter within minutes whereas their full anti-depressant effect is seen only after three to four weeks of treatment, indicating that re-uptake inhibition per se is not responsible for the antidepressant response, but rather that further adaptive changes underlie and/or contribute to their therapeutic effect. The delayed onset of anti-depressant effect is considered to be a serious drawback to currently used monoamine re-uptake inhibitors.
The compounds provided with the present invention are potent serotonin (5-hydroxy-tryptamine, 5-HT) re-uptake inhibitors. The compounds of the invention also have noradrenaline and dopamine re-uptake inhibiting activity, the serotonin re-uptake and the noradrenaline re-uptake inhibiting activity of the compounds of the invention being stronger than the dopamine re-uptake inhibiting activity of the compounds, see table below.
A strong dopamine re-uptake inhibiting activity is currently considered with the risk of undesirable central stimulating effects. On the other hand, an activating effect on the mesolimbic dopamine system is currently believed to underlay the commen mechanism of current antidepressant treatment by a mechanism which enhances the endogenous reward system. Compounds with a strong serotonin re-uptake inhibiting activity combined with a well balanced moderate dopamine re-uptake inhibiting activity may therefore provide agents with a rapid onset of anti-depressant effect.
The serotonergic neural system of the brain have been shown to influence a variety of physiologic functions, and the compounds of the present invention are predicted to have the ability to treat in mammals, including humans, a variety of disorders associated with this neural system, such as eating disorders, depression, obsessive compulsive disorders, panic disorders, alcoholism, pain, memory deficits and anxiety. Therefore, the present invention also provides methods of treating several disorders linked to decreased neurotransmission of serotonin in mammals. Included among these disorders are depression and related disorders such as pseudodementia or Ganser's syndrome, migraine pain, bulimia, obesity, pre-menstrual syndrome or late luteal phase syndrome, alcoholism, tobacco abuse, panic disorder, anxiety, post-traumatic syndrome, memory loss, dementia of ageing, social phobia, attention deficit hyperactivity disorder, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, disorders of sleep, autism, mutism or trichotillomania.
In addition, compounds with dopamine re-uptake inhibiting activity are also considered useful for the treatment of Parkinsonism, depression, obesity, narcolepsy, drug addiction or misuse, attention-deficit hyperactivity disorders and senile dementia. Dopamine re-uptake inhibitors enhances indirectly via the dopamine neurones the release of acetylcholin and are therefore useful for the treatment of memory deficits, e.g. in Alzheimers disease and presenile dementia, and chronic fatigue syndrome. Noradrenaline re-uptake inhibitors are considered useful for enhancing attention, alertness, arousal, vigilance and for treating depression.