a2 adrenergic receptors act as autoreceptors for NE neurons in much the same way that 5-HT1 receptors regulate serotonergic neurons. Thus, antagonism of a2 receptors would prevent the negative feedback NE exerts on its own synthesis, neuronal firing, and release . a2 antagonism also results in increased extracellular dopamine, acetylcholine, and 5-HT levels in vivo in rats and humans . It has therefore been proposed that a combination of SERT inhibition and a2 antagonism could result in rapid-onset antidepressant action, and possibly increased
efficacy. Clinical studies using yohimbine and other a2 antagonists in combination with SSRIs support these hypotheses .
SAR studies that began with a lead found by random screening led to compounds such as 13 (a2A K; = 0.3, SERT K; = 4.5 nM) and 14 (a2A K; = 2.4, SERT K; = 8.9 nM) that are good candidates for further in vivo characterization .
Advances in the development of selective serotonin receptor modulators was recently reviewed . Although several subtypes of 5-HT receptors may have roles in depression and anxiety, only the 5-HT1 family, 5-HT2C and 5-HT7 receptors will be highlighted here.
Serotonergic neurotransmission is controlled by three autoreceptors, the 5-HT1A and 5-HT1D receptors (mentioned above) and the 5-HT1B receptor, which limits the synthesis and release of 5-HT from the nerve terminal. It is hypothesized that a drug that antagonizes all three autoreceptors simultaneously would acutely mimic their chronic desensitization. The resulting immediate and sustained increase in levels of synaptic 5-HT should translate into a rapidly acting antidepressant . Compound 15 (pK for 5-HT1A, 1B, 1D = 8.9, 9.0, and 9.2, respectively) showed in vivo effects in models indicative of 5-HT1B antagonism and is undergoing testing in preclinical depression models .
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