5-HT1A receptor partial agonist

Depression 5-HT1A partial agonists 5-HT2 and 5-HT3 antagonists have anxiolytic properties 5-HT1A receptors are functionally sensitized by chronic antidepressant treatments in rats 5-HT2 receptor numbers are increased and activity decreased, in depression return to control values in response to treatment... 

Albert PR, Sajedi N, Lemonde S, Ghahremani MH. Constitutive Ga dependent activation of adenylyl cyclase type II by the 5-HT1A receptor. Inhibition by anxiolytic partial agonists. J Biol Chem 1999 274 35,469-35,474. 

Gettys TW, Fields TA, Raymond JR. Selective activation of inhibitory G protein alpha-subunits by partial agonists of the human 5-HT1A receptor. Biochemistry 1994 33 4283-4290. 

The best known member of this class is 8-OH-DPAT (Table 1). For more than a decade 8-OH-DPAT is the most frequently used tool to characterize 5-HT receptors [7], 8-OH-DPAT displays a high affinity for 5-HT1A receptors and weak (or no) affinity for other 5-HT receptor subtypes or transmitter receptors tested [8,4]. 8-OH-DPAT is a racemate, but the compound and its enantiomers are all potent 5-HT1A ligands [9] (Table 1). In functional tests, however, the enantiomers behave differently (R)-8-OH-DPAT is a full agonist and (S)-8-OH-DPAT is a partial agonist [1]. 

Substitution at C-l of the non-aromatic ring of tetralin with methyl introduces high stereoselectivity. Of the C-l-methylated 8-OH-DPAT enantiomers, only cis (2R)-3 displays high affinity for 5-HT1A receptors (Table 3). The antipode cis (2S)-4 is hardly active. The trans racemate (5,6) shows low affinity [9]. Cis (2R)-3 however is not selective for 5-HT receptors. The compound displays also affinity for dopamine D2 receptors. In functional tests cis (2R)-3 behaves as a mixed partial 5-HTjA receptor agonist/D2 receptor antagonist [22]. 

The benzodioxane moiety can be replaced by a variety of other heterobicyclic rings without loss in affinity [60]. A recent example is SDZ 216-525. This compound in which the N-4 of the indolepiperazine is substituted with the saccharinebutyl chain of ipsapirone is a potent and rather selective antagonist at postsynaptic 5-HT1A receptors [61] (Table 12). At the somatodendritic 5-HT1A autoreceptors SDZ 216-525 behaves as a partial agonist [62],... 

An other aminomethylbenzdioxan containing 5-HTlA ligand is the antipsychotic spiroxatrine. This compound displays a high affinity for the 5-HT,A affinity (pKi=9.1) but is not selective with respect to various other receptors, such as dopamine D2 (pK1=9.0), morphine p (pKj=8.2) receptors, and a,-adrenoceptors (pKj= 7.1) [47] Table 13. Spiroxatrine is a racemate. The affinity for 5-HT1A receptors resides, similar to MDL 72832, mainly in the S(-)-enantiomer [64], In functional tests spiroxatrine acts as a partial agonist [3]. 

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