Chapter 24

The opioid analgesics아편 관련 -

Pain

• Classification:– Nociceptive 통증감지

– Inflammatory 염증

– Pathological 균 , 바이러스

– Neuropathic 신경자체에 손상이 생겨서계속 통증이 지속되는 질병

– Psychogenic정신적인 이유에 의해서 통증 유발 ( 정신적 충격 , 불안 , 우울 등등 )

Nociception

• Pain receptors – nociceptors: sensory neurons• 일종의 neuron 과 똑같은 역할 • 자극에는 threshold 존재 일정한 수위를 넘기지 않으면 자극 전달 X

약을 먹었다거나 물질이 직접적으로

피부에 닿았을 경우에

압력 , 물리적인 원인으로 통증유발

빛에 반응해서 신호를 전달

배운 대부분의 receptor 가 trans-mission 에 관여를 주로 한다 .

Ex) serotonin

Analgesics (aka painkillers)

약국에서 흔한 약한 opioid ( 근데 opioid 가 현존하는 제일 강한 진통제임 )

제일 강력크한 진통제 완전 다 써보고 제일 마지막 방도로 사용하는 것들

Analgesics (aka painkillers)• NSAIDs (Non-steroidal anti-inflammatory drugs): aspirin, ibuprofen• Opiates - Narcotic analgesics that are structurally related to morphine

= 강력 진통효과 • Opioids – synthetic/semi-synthetic/naturally occurring

endogenous compounds that interact with opioid receptors in the body= 기본적으로 몸속에도 자연적으로 존재함

• Opium – the oldest herbal medicine known to humanity= 인류역사상 가장 오래된 약 (?)

• Effective treatment for diarrhea ( 설사 치료제 )• Powerful sedative ( 가장 강한 진정제 )• Active principle: morphine (chemical)

= 의사들만 처방이 가능하고 키우거나 파는건 불법 . = 철저히 의료용으로만 유통 합법

Morphine

• First isolated in 1803• T 자 구조 형태—최적의 receptor—ligand interaction 을 보이는 형태

oral availability 가 너무 안 좋음• Potent analgesic and sedative• Drug of choice for severe pain: elevating pain threshold• Addiction, tolerance, and dependence ** 부작용 **• ( 환각 , 변비 , 흥분 )

호흡중추억제 ( 숨안쉬게됨 )통증이 극심한 사람들만 사용가능하고 , 특히 임산부는 사용하면 아기가 산소공급이 안되기 때문에 죽을수도 , 기형아가 되거나 ㅇㅇ

Structure-activity relationship of morphine이게 어떻게 생겨먹었는지 한번 보자 .

VDW interxn!

이 세가지중에 어느하나가 없어지면 activity ⇩Stereochemistry 변형 activity⇩

위치도 중요 !**

위치도 위치지만 세 가지의 상대적인 위치도

중요

H— 의 위치에 따라서 전체적인 구조가 바뀜

Respiratory depression ⇩ ( 부작용 ⇩ )— 진통 효과 ⇩

K agonist 만들었더니 환각 / 정신병 유발 진통이랑 sedation clinically 중요 X

DOR

KOR

NOR

MOR• 진통 / 효과 ⇧ , 중독성 ⇧ ****• r. Depression ⇧ = 변비 = 장운동 멈춤• 적응증 , dependence = 같은 약효과를 낼수 있는 dosage ⇧

• 식용관련 비만 치료제로 사용가능

Opioid receptors (GPCR, GPLR = 3 가지 type) • Three different analgesic receptors (mu, kappa and delta)• Binding sites for all three receptors contain ionic, hydrogen bonding and

hydrophobic regions as proposed by Beckett- Casy• Activation of all three produce analgesia, but differ in other effects• All three interact with morphine• Potential to target drugs selectively

가장 기본적인 pharmacophore 는 동일 **선택성 , 진통제역할이 높은 것을 개발중

μ 제일 효과가 좋음 .

Mu Receptor ()• Morphine binds strongly• Activation produces anal-

gesia plus side effects (respiratory depression, euphoria, addiction)

• G-Protein coupled recep-tor

• -Receptor subtypes have been pro-posed which may allow separation of analgesia from side effects

• -Receptors related to all sources ofpain stimuli

< 효과가 전부 심하게 일어남 >- 저 용량에서도 r. depression 이 일어나서

죽을 수 있다 .- 모든종류의 pain 에 관여하고 - 열 , 때리는 실험 , 얼음물 뒤집어 쓰기 등등

을 사용해서 진짜 pain 을 느끼는지 아닌지 구분함 . 그 통증의 강도라던지 .

Kappa Receptor ()• G-Protein-coupled receptor (GDCR)• Morphine binds less strongly• Receptors related to non-thermal pain in-

duced stimuli ( 진정 , 졸음 )• Activation produces analgesia plus sedation• Potential target for safe analgesics (com-

pounds acting as agonists at , antagonists at and no activity at the receptor)

• 정신불안 , 정신병효과가 있어서 중단• But psychotomimetic side effects (anxiety,

depression, psychosis)• μ >>> k 결합 강도• ** r. depression (X)

Delta Receptor ()• Morphine binds strongly• Receptor for enkephalins (natural pain killers)• Activation produces analgesia plus some side effects• G-Protein-linked receptor• receptors related to pain induced stimuli from all

sources

Morphine: pharmacodynamics and pharmacokinetics

Morphine with some masking

BBB 통과 못함 . (ioninc)Me disappearedstill ionic because of the amine present

codeine = 많이 쓰임—기침억제제

Morphine analogues

u antagonistK agonist— 부작용 *

Allyl, cyclopropylmethyl Antagonist 특징

해독제 작용 , 술이 mor-phine receptor 자극 , 알콜중독치료제—진통효과⇩Antagonist [u]

나중에 또 나옴

• Morphinans are more potent and longer acting than their morphine counterparts, but also have higher toxicity and comparable dependence characteristics

• Changes on morphinans have the same biological effect as those carried out on morphine.same receptor interactions and binding (morphinan receptor = morphine receptor)

• 장점 : Simpler molecules and easier to synthesize• 특징 : [D ring, —OH, C ring double bond] 제거• Levallorphan(x5) >> nalorphine

Simplified morphine analogues: Morphinans

Simplified morphine analogues: Benzomorphans

• Rings C and D are not essential— 진통제 역할 X• Analgesia & addictiveness co-existant (X)• WHAT’s NEEDED:

good analgesic activityless addictive liabilityless tolerance

• Simpler to synthesize• Interact with target binding sites [same as morphine]

Bremazocine contains psy-chotomimetic side effects효과가 좋아도 특정부작용이 심각addiction⇩, r.depression⇩

Simplified morphine analogues: Phenylpiperidines** 링이 많이 없어짐

30*20% = 모르핀보다 6 배

• 특징1. N 이 껴져있는 링 구조 = piperidine2. Phenol group X, BCD+OH 제거3. Ester group present4. N-Allyl or cyclopropyl groups = X antagonist 5. Implies different receptor interactions6. More flexible molecules may allow different

binding modes7. Very easy to synthesize• 단점 **

1.

Simplified morphine analogues: 4-anilinopiperidines** 가장 강력한 진통효과 (Et 이외— OH 없음 )

• 특징 :1. 쎈놈 : receptor—agonist2. Highly lipophilic and efficiently cross BBB—

통과량이 많아서 뇌내 효과⇧3. X100 more active than morphine4. Used during surgery for analgesia and to

enhance anaesthesia5. ABCD—ring(X), [N, ketone] 추가

• 단점 :1. Prone to rapid metabolism (short-duration)2. 대사가 너무 빨리 되어서 수술 중에

진통효과를 위해서 사용함

Simplified morphine analogues: Methadone

Anti-diarrheal agent 설사 치료제

절반 methadone, hybrid struc-ture구조상 BBB 통과 불가능 그래서 장에서만 작용함 .

• 특징 :1. All rings disappear2. Diphenyl propyl amine structure3. 진통 (+++), 경구투여 , 진정효과 (+)4. ⇩emetic, constipation, euphoric,

금단현상5. 모르핀 , 헤로인 중독 치료에 사용

• 단점 :1. R. depression, dependence2. Flexible molecule—rotation 가능3. Different from 모르핀4. 장점이자 단점 ; BBB 통과 X

Morphine analogues: rigidification링묶어서 고정해주는거 (rotation prevention)

• Less flexible structures• More active if active conformation is retained• Possibly less side effects• Better oral absorption• Less easy to make

Antagonist 진통효과 X

Buprenorphine

• Partial agonist for the receptor(**partial) & antagonist for the , receptors

• Clinically useful analgesic 부작용이 적어서 *• No euphoria or addiction liability• Crosses the BBB easily• Low dependence potential• Lower respiratory depression• Longer duration 지속 up, 약효 up

why? receptor 에 결합하기 까지 , receptor 에서 떨어지기까지가 오래걸림

therefore: 개복수술 , 암환자에게 사용단점 **• Dissociates slowly from the receptor (gradual effects)• Not effective for severe pain• Can NOT be taken orally due to rapid metabolism ( 대사가 너무 빨리 되어서 )• Side effects (drowsiness, nausea and dizziness)

Specific receptors have additional hydrophobic binding regions which lead to agonist or antagonist activity.

Agonist

Antagonist

Agonists vs Antagonists

Why should small changes in structure (e.g. N-methyl to N-allyl) change an agonist to an antagonist at a specific receptor?

Agonists vs AntagonistsHow do we explain the fact that some opioids act as an agonist with one type of opioid receptor, and as an antagonist at another?

Agonist

Antagonist

The relative positions of the extra hydrophobic regions are different in the different types of receptor

Endogenous opioid peptides and opioids지금까지는 synthetic 한거만 봤으니까 이제 자연적인거 봄 .

Body’s natural painkillersPentapetide structure

Endogenous opioid peptides and opioids

Enkephalins= 머리속

• Endogenous peptides acting as neurotransmitters in brain• Enkephalin - Greek for ‘in the head’• Bind to opioid receptors with some selectivity for delta

receptors ()• At least 15 endogenous peptides of 5-26 AA’s (endor-

phins andenkephalins). All contain Met or Leu encephalin sequences at the N-terminus

• Biosynthesized from inactive protein precursors (proenkephalin, prodynorphin etc)

• Inactivated by peptidase enzymes in vivo (orally inactive) -hydrolyzed between Tyr and Gly ( 위에서 분해 )

H-Tyr-Gly-Gly-Phe-Met-OH

SAR = piperidine 계통의 물질들

• Tyrosine essential for activity (phenol group and N)• Phenol group of Tyr thought to be equivalent to phenol group of

morphine• Tyr nitrogen thought to be equivalent to morphine nitrogen• Aromatic ring of Phe important (additional interaction)

AnaloguesAIM ( 큰목표 , 목적 )To synthesise analogues which are stable to peptidases and which would be orally active

STRATEGY 이걸할수있는 방법 ?Replace non-essential amino acids with unnatural AA’s or D-AA’s to make enkephalin unrecognizable to peptidasesD—form 으로 바꿔주면 인식 불가능해서 사용가능

-Selective Enkephaline Analogues

Enkephalinase (enzyme) Inhibitor: Thiorphan

Racecardotril (Acetor-

phan) pro-drug 형태 !

anti-diarrheal drug

Receptor—bind-ing site

Leads to the tar-get

너무 reactive 해서 prodrug 형태 필요함

Main effects of opioids at opioid receptors

Blue = Agonist(Blue) = Partial agonist

Red = Antagonist

Endogenous peptides

-endorphin +++ +++ +++Leu-enkephalin + +++ -Met-enkephalin ++ +++ -Dynorphin ++ + +++Opiate drugs

Pure agonists

Morphine, codeine +++ + +Methadone +++ - -Pethidine ++ + +Etorphine +++ +++ +++Fentanyl +++ + -Partial/mixed agonists

Pentazocine + + ++Nalorphine ++ - (++)Buprenorphine (+++) - ++Antagonists

Naloxone +++ + ++Naltrexone +++ + +++

등장 X agonists

The future of opioids research• Recent research aims at developing selective opioids for a type of receptor• Holy Grail – potent, orally active opioid analgesic without side effects• The oldest drugs used in medicine, but the least understood

Tissue-specific dimer formation

MDAN-21

Mu selective진통효과 upAddiction downDependence X

antagonist

Design of Nalfurafine– Peripheral-acting opioids (No CNS effects)

• K receptor may form K,K-homodimer in periphery• K-K distance is shorter than other homodimers – an opioid

dimer with a shorter linker can be a k selective agonist?

Simplification (but, still bulky…)

Naltrexone dimer

Design of Nalfurafine– Peripheral-acting opioids (No CNS effects)

No psychotomimetic effectsSedation Alleviate local itchingClinically used for uremic pruritus in Japan