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D21
B

Primary Mechanism D1-D2 Dimer Blocker
Class Nootropic
Drug Status Experimental
Alternate Names TAT-D21, TAT-D1-D2
Pubchem ID None/Unknown
Contributors @arche, @yana
Smiles: Unavailable
IUPAC: Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Pro-Gln-Gly-Ser-Ser-Glu-Asp-Leu-Lys-Lys-Glu-Glu-Ala-Ala-Gly-Ile-Ala-Arg-Pro-Leu
CAS: None/Unknown

Pharmacology

D21, AKA TAT-D1-D2, is an endogenously derived heteromer modulating peptide which modulates dopamine receptor dynamics and function. It may be classed as a nootropic, or antidepressant.

D21 has been typically though to block the interaction between D1 and D2 receptors, inhibiting D1-D2 heteromer expression and function without affecting other receptor oligomers such as D1-D1 homomers or D2-D5 heteromers. D1 and D2 forming a dimer has been disputed to some degree [4], however there is more evidence for it than against it.

It is possible that blocking the D1-D2 dimer (with D21) essentially ‘differentiates’ D1 and D2 and allows much more flexible LTP and LTD that is seen in adolescence (as D1-D2 heteromer prevelance increases with age [7]). D21 also potentially modulates dopamine-induced hypofrontality.

The D1-D2 heteromer is much more prevalent (~250% d21/d1 ratio compared to control) in those with Depression, meaning it is a potential target for depression.

In animal models, D21 treatment alleviates behavioural despair symptoms and exerts antidepressant-like effects in rats [1], and in addiction models the D21 reverses SKF83959-induced inhibition of amphetamine sensitization [3].

High dopamine levels preferentially make the D1-D2 heteromer inhibit D1 signalling, whilst low dopamine levels make the heteromer inhibit D2 signalling [2][4]: "Upon treatment of 10 nM dopamine, D1-D2 heterodimer induces a similar level of cAMP to D1 only (possibly because D2 activity in the heterodimer is inhibited at this nanomolar DA level) In contrast, at 10 µM dopamine, the cAMP level by D21 was significantly lower than the one by D1."

D21 has also been found to:

  • Elevate BDNF in the Prefrontal Cortex
  • May also modulate or inhibit BDNF transcription contextually [5]
  • Lowered locomotor activity (without being anti-immobility) [1]

D21 is a very large peptide with a molecular weight of 3472.97 due to it being a peptide 30 amino acids long, meaning pharmacokinetics could be more ideal.

The ideal ROA for D21 is most likely intranasal.

Sources

[ 1 ] Intranasal Delivery of a Peptide with Antidepressant-Like Effect
[ 2 ] Differential receptor crosstalk in DRD1-DRD2 heterodimer upon phasic and tonic dopamine signals
[ 3 ] The dopamine D1-D2 receptor heteromer exerts tonic inhibitory effect on the expression of amphetamine-induced locomotor sensitization
[ 4 ] Evidence against dopamine D1/D2 receptor heteromers
[ 5 ] Dopamine D1-D2 receptor heteromer signaling pathway in the brain: emerging physiological relevance
[ 6 ] Visualization of differential GPCR crosstalk in DRD1-DRD2 heterodimer upon different dopamine levels
[ 7 ] Reduced striatal dopamine D1-D2 receptor heteromer expression and behavioural subsensitivity in juvenile rats

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