P21-Adamantane

Technical data

INN name

P21 (Peptide 021)

Development code

P021

CAS

1246751-68-7

Molecular formula

C27H42N6O8

Molecular weight

578.67 g/mol

Identity and composition

P21-Adamantane (P021 / Peptide 021) is a low-molecular-weight peptide mimetic derived from ciliary neurotrophic factor (CNTF), studied in preclinical research for its activity on neurogenesis and synaptic plasticity. It is a short peptide modified with an adamantane residue. Product for research use.

From the standpoint of chemical identity, the literature consulted confirms:.

• Molecular formula: C27H42N6O8 (confirmed in PubChem CID 56589645, 'Peptide 021'). Note: some supplier catalogs list a different formula (C30H54N6O5) for the Ac-DGGLAG-NH2 form; this discrepancy between sources is unresolved. - Sequence: Ac-DGGLAG-NH2, with an adamantylated C-terminal glycine (gamma-aminoadamantane-1-carbonyl), derived from residues ~148-151 of CNTF. The PubChem IUPAC structure corresponds to the Ac-Asp-Gly-Gly-Leu core conjugated to 3-carbamoyl-1-adamantyl. - CAS: 1246751-68-7 appears in PubChem but is flagged as an obsolete/'removed' synonym; it should be treated as tentative, not confirmed as active CAS. - Synonyms: P021, P21, Peptide 021, Ac-DGGLAG-NH2, GLXC-21260, peptide mimetic of CNTF.

El molecular weight is not shown in the open PubChem entry and the supplier value is not confirmed in an authoritative source, so it is omitted.

Reference presentation: 10 mg.

Mechanism of action

P21-Adamantane was designed as a peptide mimetic of the active region of CNTF. From the neurogenic 11-mer of CNTF, a short fragment (Ac-DGGLAG-NH2) was truncated, into which an adamantane residue is incorporated at the C-terminal glycine. This adamantane portion, highly lipophilic, was added with the aim of improving metabolic stability, resistance to proteases, and penetration of the blood-brain barrier.

In the preclinical literature it is described that P021 increases BDNF expression and partially inhibits the leukemia inhibitory factor (LIF)/STAT3 signaling pathway, which in these models is associated with promotion of neurogenesis in the dentate gyrus, maturation of newly formed neurons, and synaptic plasticity (PMID 20600002; PMID 39592934).

It is important to emphasize that all mechanistic characterization is in vitro and in animal models, and that the observed effects are not uniform across models.

Pharmacokinetics

None were located verifiable numerical pharmacokinetic parameters (half-life, Cmax, bioavailability) in the open primary sources, so no figures are reported.

Qualitatively, the literature describes that the adamantane design sought to confer greater metabolic stability and blood-brain barrier permeability compared with full-length CNTF (which crosses the barrier poorly, is unstable in plasma, and induces antibodies). Activity after peripheral administration in rodents, including the oral route, is also mentioned. These parameters must be treated as not quantified.

Scientific evidence

P21-Adamantane is a compound exclusively for preclinical research. No registered human clinical trials were identified (a ClinicalTrials.gov search yielded no results attributable to P021/P21), so the evidence should be read as preliminary and limited to models.

The foundational work investigated improvements in learning/memory and neurogenesis after peripheral administration in normal adult mice (PMID 20600002). Subsequent studies have explored the compound in models of Alzheimer's disease (e.g., 3xTg-AD), aging, Down syndrome and CDKL5 deficiency disorder.

The results are mixed: in a model of CDKL5 deficiency, P021 rescued neuronal deficits in culture, but chronic in vivo treatment did not increase BDNF or correct the neuroanatomical defects, which tempers any claim of generalized efficacy (PMID 39592934). The 'studied' indications must be understood as preclinical hypotheses, not as approved uses.

Research applications

Product for research use.

Ideal for:

• In vitro and animal-model studies on neurogenesis, neuronal maturation, and synaptic plasticity.
• Exploratory research on peptide mimetics of CNTF-derived neurotrophic factors.
• Comparative work within the class of low-molecular-weight peptides targeting neurotrophic pathways.

Not applicable for:

• Any form of clinical use, diagnosis, treatment, or prevention of diseases.
• Clinical or therapeutic use: there is no regulatory profile or safety data in humans.
• Extrapolating results from animal models to outcomes in humans.

Research protocols

The literature reviewed does not include mg dose figures used in the studies that can be supported with a specific citation, so no numerical dosing protocols are reported.

Qualitatively, the preclinical literature describes peripheral administration (including the oral route in rodents) in the models investigated (PMID 20600002). Any experimental design of dose, route and frequency remains at the discretion of the investigator and must be based on the pertinent primary literature and on the practices of their protocol, not on this data sheet.

Reconstitution

As a standard general laboratory guideline for a lyophilized peptide:

• It is usually reconstituted with bacteriostatic water (sterile water with ~0.9% benzyl alcohol), which helps limit microbial growth in preparations for repeated use.
• Add the diluent slowly down the wall of the vial, letting it run over the lyophilized material; do not inject it directly onto the powder.
• Do not shake: swirl the vial gently until complete dissolution to reduce mechanical stress on the peptide.
• Adjust the diluent volume to the desired working concentration according to your experimental design (reference presentation: 10 mg).

Given the lipophilic adamantane component, visually verify complete dissolution before use.

Stability and storage

General laboratory handling guide:

• Lyophilized (powder): is the most stable form. It is usually stored refrigerated for short-term use and frozen for prolonged storage, protected from moisture and light. - Reconstituted (in solution): must be kept refrigerated and be used within a relatively short time; for longer periods it is usually divided into aliquots and frozen. - Avoid repeated freeze-thaw cycles, which degrade peptides; prepare single-use aliquots whenever possible. - Minimize exposure to room temperature and to light during handling.

These are standard handling practices; the consulted literature does not provide specific stability data for the compound.

Safety profile

There are no safety data in humans for P21-Adamantane, nor a regulatory safety profile. Use is strictly 'for research use only'.

In preclinical models it is described as well tolerated after chronic peripheral administration and, unlike full-length CNTF, without antibody formation. However, no verifiable formal toxicological studies were located, so this characterization is limited.

Because it is research material without an established toxicological profile, it must be handled with adequate personal protective equipment and under the laboratory's biosafety practices. There are no documented clinical contraindications because there is no defined clinical use.

Comparative context

Compared to the Full-length CNTF (~22.8 kDa), P21-Adamantane is a small peptide (tetra/hexapeptide) designed to retain the neurogenic/neurotrophic activity of the active region of CNTF while improving penetration of the blood-brain barrier, metabolic stability and avoiding the immunogenicity associated with full-length CNTF.

Within the class of low-molecular-weight peptide mimetics of neurotrophic factors, shares targets with other compounds directed at the BDNF/TrkB axis, but is distinguished by:

• Su originating from CNTF (not directly on BDNF).
• Su modification with adamantane, which gives it the desired lipophilic character.

Any notion of 'superiority' must be considered specific to preclinical models and not uniform, as illustrated by the negative in vivo result in the CDKL5 deficiency model (PMID 39592934).

History and development

P21-Adamantane (P021) was developed in the laboratory of Khalid Iqbal, at the New York State Institute for Basic Research. Its design started from the neurogenic 11-mer of CNTF (Ac-VGDGGLFEKKL-NH2, known as 'P6'), which was truncated to a short fragment (Ac-DGGLAG-NH2). An adamantane residue was incorporated at the C-terminal glycine of this fragment to improve metabolic stability and penetration of the blood-brain barrier.

The foundational study (FEBS Lett 2010; PMID 20600002) described improvements in learning/memory, neurogenesis, and synaptic plasticity after peripheral administration in mice. Subsequent research has explored the compound in models of Alzheimer's, aging, Down syndrome, and CDKL5 deficiency, with mixed results that maintain its status as preclinical research compound.

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Scientific references (3)

Peer-reviewed literature on P21-Adamantane, with its PubMed identifier where available:

• Neurotrophic peptides incorporating adamantane improve learning and memory, promote neurogenesis and synaptic plasticity in mice (Li, et al. · FEBS Letters · 2010) PMID 20600002.
• Neurotrophic Treatment Initiated During Early Postnatal Development Prevents the Alzheimer-Like Behavior and Synaptic Dysfunction (Wei, et al. · Journal of Alzheimer's Disease · 2021) PMID 34057082.
• Prevention of dendritic and synaptic deficits and cognitive impairment with a neurotrophic compound. (Baazaoui N, et al. · Alzheimers Res Ther · 2017) PMID 28655344.

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