Small molecular compound SPAM1 for up-regulating neuropeptide PACAP and receptor PAC1-R thereof and preparation method and application thereof

A technology of small molecular compounds and neuropeptides, applied in nervous system diseases, medical preparations containing active ingredients, drug combinations, etc., can solve the problems of limitation, poor in vivo stability of PACAP, limited function of crossing biological barriers, etc. Small effect with few side effects

Pending Publication Date: 2020-08-14
余榕捷 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although PACAP has potential anti-aging pharmaceutical development value, in view of the extremely poor stability of PACAP in vivo, for example, the half-life of PACAP38 in vivo is less than 2min, and its function of crossing biological barriers is limited, so it is extremely difficult to directly develop PACAP into a drug limits

Method used

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  • Small molecular compound SPAM1 for up-regulating neuropeptide PACAP and receptor PAC1-R thereof and preparation method and application thereof
  • Small molecular compound SPAM1 for up-regulating neuropeptide PACAP and receptor PAC1-R thereof and preparation method and application thereof
  • Small molecular compound SPAM1 for up-regulating neuropeptide PACAP and receptor PAC1-R thereof and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: the pilot test synthetic technique (two-step method) of SPAM1

[0038]according to figure 1 As shown, a two-step synthesis was adopted. Step 1: In a 150 mL flask equipped with a condenser, benzamide A (5.45 g, 40.0 mmol, 1.0, etc.) and amber hydride B (4.00 g, 40.0 mmol, 1.0, etc.) were mixed in 50 mL of toluene middle. The suspension was vigorously refluxed for 3 hours and then cooled to room temperature. The resulting product C was filtered as a white solid, washed with Et2O and dried (8.833 g, 88.3% yield). Product NMR detection as figure 2 shown.

[0039] Step 2: Synthesize according to the following feeding ratio:

[0040] project code C D E F EDCI DCM Source number (g) 10.00 5.82 6.51 13.07 9.08 200mL Molar equivalent (eq) 1.0 1.0 1.0 3.0 1.1 20mL / g

[0041] At room temperature, add C and D successively to the 500mL reaction flask, then add the solvents DCM and F, and stir. Add shrinkage agent ED...

Embodiment 2

[0042] Example 2: SPAM1 effectively up-regulates the level of PACAP in the body

[0043] 30 BALb / c mice, SPF grade, 8-10 weeks old, 22-27g in weight, half male and half male, were randomly divided into 3 groups, 10 mice in each group: 1) SPAM1 low-dose group, intraperitoneal injection of 10umol / kg ; 2) SPAM1 high-dose group, intraperitoneal injection of 100umol / kg; 3) normal control group, intraperitoneal injection of normal saline; 30 minutes after injection, blood was collected from the orbit, and the serum was detected by ELISA kit for PACAP. The result is as Figure 4 As shown, SPAM1 effectively up-regulates the content of PACAP in serum, and the up-regulation effect is concentration-dependent.

Embodiment 3

[0044] Example 3: SPAM1 effectively up-regulates the expression of PACAP-specific receptor PAC1-R

[0045] Neuro2a, a mouse neuron cell naturally expressing PAC1-R, was cultured until the fusion rate was above 80%, and 1uM-100uM SPAM1 was added, and after incubation for 1h, the cells were broken; the supernatant of the whole cell lysate was subjected to SDS-PAGE and anti-PAC1- The antibody at the C-terminal of R was detected by western blot. The result is as Figure 5 As shown, 1uM, 10uM and 100uM of SPAM1 up-regulated the expression of PAC1-R in nerve cells in a concentration-dependent manner.

[0046] The human nerve cell SHSY-5Y that naturally expresses PAC1-R was cultured to a fusion rate of over 80%. After incubation with 100uM SPAM1 for 1 hour, confocal immunofluorescence observation was performed: DAPI staining of the nucleus was purple blue, while the red color targeting PAC1-R The fluorescent signal was significantly upregulated by SPAM1 ( Figure 6 ).

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Abstract

The invention discloses a small molecule compound SPAM1 for up-regulating neuropeptide PACAP and receptor PAC1-R thereof and a preparation method and application thereof. The structure of the small molecule compound SPAM1 is as shown in formula (I), and R = none or H20 or HCl; the SPAM1 is small in molecular weight, and can efficiently pass through biological barriers including a blood brain barrier, a blood testis barrier and the like; expression of neurotransmitter / conditioned PACAP secreted by hypothalamus-pituitary gland and a specific receptor PAC1-R of the neurotransmitter / conditioned PACAP acts on downstream glands of a gonad axis and an adrenal axis so that the regulation and control effects of the neurotransmitter / conditioned PACAP are comprehensive; the SPAM1 specifically targetsPAC1-R1, only acts on cells and tissues for naturally expressing a PAC1-R nervous system and an endocrine system, and is relatively small in side effect. Therefore, the SPAM1 will become a novel small-molecule compound medicine for effectively treating and preventing functional aging and disorder of the nervous system, the endocrine system and the immune system which are closely related to the neuropeptide PACAP.

Description

technical field [0001] The present invention relates to the fields of chemistry and biochemistry, in particular to a small molecule compound SPAM1 that effectively up-regulates the expression of neuropeptide pituitary adenylate cyclase activating polypeptide (pituitary adenylate cyclase activating polypeptide, PACAP) and its specific receptor PAC1-R : 4-((4-(4-oxo-3,4-dihydroquinazolin-2-yl)butyryl)methylbenzoic acid and its derivatives, the efficient preparation method of SPAM1 and its role in prevention and treatment and The application of PACAP and its specific receptor PAC1-R to the nervous system, endocrine system, and immune system in physiological and pathological diseases and functional decline. Background technique [0002] The neuropeptide PACAP, which was originally isolated from the bovine hypothalamus-pituitary gland, belongs to the superfamily of vasoactive intestinal peptide / secretin / growth hormone releasing hormone / glucagon; PACAP is an extremely conserved ac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/88A61K31/517A61P25/00A61P3/00A61P37/02A61P39/00A61P31/00
CPCA61P25/00A61P37/02C07D239/90A61P5/00
Inventor 余榕捷
Owner 余榕捷
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