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SEÇÃO 1� � PRINCÍPIOS GERAIS
 Como agem os fármacos: 
aspectos moleculares 3 
 CONSIDERAÇÕES GERAIS 
 Neste capítulo, passamos dos princípios gerais da 
ação dos fármacos esboçados no Capítulo 2 às 
moléculas que estão envolvidas no reconhecimento 
dos sinais químicos e em sua tradução em respostas 
celulares. A farmacologia molecular vem avançando 
rapidamente, e o novo conhecimento está mudando 
nossa compreensão sobre a ação dos fármacos e 
também abrindo muitas novas possibilidades tera-
pêuticas, discutidas mais adiante, em outros capítulos. 
 Em primeiro lugar, consideraremos os tipos de 
proteínas-alvo sobre as quais os fármacos agem. 
A seguir, descreveremos as principais famílias de 
receptores e canais iônicos que foram reveladas por 
clonagem e estudos estruturais. Por fi m, discutire-
mos as várias formas de conexão receptor-efetor 
(mecanismos de transdução de sinal) por meio das 
quais os receptores são acoplados à regulação da 
função celular. A relação entre estrutura molecular 
de um receptor e sua ligação funcional a um tipo 
particular de sistema efetor é o tema principal. Nos 
próximos dois capítulos, veremos como esses eventos 
moleculares alteram aspectos importantes da função 
celular – uma base útil para a compreensão dos efei-
tos dos fármacos sobre organismos vivos íntegros. 
Aprofundamos em mais detalhes do que o neces-
sário para entender a farmacologia de hoje em nível 
básico, com a intenção de que os estudantes possam, 
caso queiram, pular ou ler superfi cialmente esses 
capítulos sem perder o fi o da meada; no entanto, 
estamos convictos de que a farmacologia de ama-
nhã estará solidamente alicerçada nos avanços da 
biologia celular e molecular aqui discutidos. 
 ALVOS PARA A AÇÃO DE FÁRMACOS 
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GHVVHV�WLSRV�GH�SURWHtQD��PDV�H[LVWHP�H[FHo}HV��3RU�H[HPSOR��D�
�FROFKLFLQD���XWLOL]DGD�QR�WUDWDPHQWR�GH�DWDTXHV�DJXGRV�GH�JRWD�
��&DS�¬������LQWHUDJH�FRP�D�SURWHtQD�HVWUXWXUDO�WXEXOLQD��HQTXDQ�
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LPXQRILOLQDV��$QWLFRUSRV�WHUDSrXWLFRV�TXH�DJHP�VHTXHVWUDQGR�
DV�FLWRFLQDV��PHGLDGRUHV�SURWHLFRV�HQYROYLGRV�QD�LQIODPDomR��
�&DS�¬�����WDPEpP�VmR�XVDGRV��$OYRV�SDUD�IiUPDFRV�TXLPLR�
WHUDSrXWLFRV����&DSV�¬����������������������������������������HP�TXH�D�LQWHQomR�p�VXSULPLU�RV�
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'1$�H�FRQVWLWXLQWHV�GD�SDUHGH�FHOXODU��DVVLP�FRPR�RXWUDV�
SURWHtQDV��
 RECEPTORES 
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WHPD�GH�FRPXQLFDo}HV�TXtPLFDV�TXH�FRRUGHQDP�D�IXQomR�
GH�WRGDV�DV�GLIHUHQWHV�FpOXODV�GR�RUJDQLVPR��VHQGR�PHQ�
VDJHLURV�TXtPLFRV�RV�YiULRV�KRUP{QLRV��WUDQVPLVVRUHV�H�
RXWURV�PHGLDGRUHV�GLVFXWLGRV�QD�6HomR���GHVWH�OLYUR��0XLWRV�
IiUPDFRV�WHUDSHXWLFDPHQWH�~WHLV�DJHP��RX�FRPR�DJRQLVWDV�
RX�FRPR�DQWDJRQLVWDV��QRV�UHFHSWRUHV�GH�PHGLDGRUHV�HQGy�
JHQRV�FRQKHFLGRV��1D�PDLRU�SDUWH�GRV�FDVRV��R�PHGLDGRU�
HQGyJHQR�IRL�GHVFREHUWR�DQWHV�²�FRP�IUHTXrQFLD��PXLWRV�
DQRV�DQWHV�²�GH�R�UHFHSWRU�WHU�VLGR�FDUDFWHUL]DGR�IDUPDFR�
OyJLFD�H�ELRTXLPLFDPHQWH��PDV��QRV�~OWLPRV�DQRV��PXLWRV�
UHFHSWRUHV�IRUDP�LQLFLDOPHQWH�LGHQWLILFDGRV�FRP�EDVH�HP�
VXDV�FDUDFWHUtVWLFDV�IDUPDFROyJLFDV�RX�PROHFXODUHV��(P�
DOJXQV�FDVRV��FRPR�R�GRV�UHFHSWRUHV�FDQDELQRLGHV�H�GRV�
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QRV�IRUDP�LGHQWLILFDGRV�PDLV�WDUGH��HP�RXWURV��FRQKHFLGRV�
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FRQKHFLGR��VH�p�TXH�H[LVWH���
 CANAIS IÔNICOS 
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SDVVDJHP�GH�GHWHUPLQDGRV�tRQV��H�TXH�VmR�LQGX]LGRV�D�VH�
DEULU�RX�VH�IHFKDU�SRU�XPD�YDULHGDGH�GH�PHFDQLVPRV��2V�
�FDQDLV�FRQWURODGRV�SRU�OLJDQWHV��H�RV��FDQDLV�FRQWURODGRV�SRU�YRO�
WDJHP��VmR�GRLV�WLSRV�LPSRUWDQWHV��2�SULPHLUR�DEUH�DSHQDV�
TXDQGR�XPD�RX�PDLV�PROpFXODV�DJRQLVWDV�VmR�OLJDGDV��H�VmR�
SURSULDPHQWH�FODVVLILFDGRV�FRPR�UHFHSWRUHV��Mi�TXH�p�QHFHV�
ViULD�D�OLJDomR�GH�XP�DJRQLVWD�SDUD�TXH�VHMDP�DWLYDGRV��
2V�FDQDLV�FRQWURODGRV�SRU�YROWDJHP�VmR�UHJXODGRV�QmR�SRU�
OLJDomR�GH�XP�DJRQLVWD��PDV�VLP�SRU�DOWHUDo}HV�QR�SRWHQFLDO�
WUDQVPHPEUDQD��
�'H�IRUPD�JHUDO��RV�IiUPDFRV�SRGHP�DOWHUDU�D�IXQomR�GRV�
FDQDLV�L{QLFRV�GH�YiULDV�PDQHLUDV��
������� ��$WUDYpV�GD�OLJDomR�j�SUySULD�SURWHtQD�GR�FDQDO��TXHU�QR�
ORFDO�GH�OLJDomR���RUWRVWpULFD���GR�OLJDQWH��TXHU�HP�RXWURV�
ORFDLV���DORVWpULFD����RX��QR�FDVR�PDLV�VLPSOHV��H[HPSOLILFDGR�
SHOD�DomR�GRV�DQHVWpVLFRV�ORFDLV�QRV�FDQDLV�GH�VyGLR�
GHSHQGHQWHV�GD�YROWDJHP���&DS�¬������D�PROpFXOD�GR�
IiUPDFR�OLJD�VH�ILVLFDPHQWH�DR�FDQDO���)LJ�¬����%��H��GHVVH�
PRGR��EORTXHLD�D�SHUPHDELOLGDGH�DRV�tRQV��2V�IiUPDFRV�
TXH�VH�OLJDP�D�ORFDLV�DORVWpULFRV�QR�FDQDO�GD�SURWHtQD�H�
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UHFHSWRU�FORUHWR�*$%$�$���XP�FDQDO�DWLYDGR�SRU�OLJDQWH��TXH�p�GLIHUHQWH�GR�ORFDO�GH�OLJDomR�GH�
*$%$��IDFLOLWDQGR�D�DEHUWXUD�GR�FDQDO�DWUDYpV�GR�
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FpOXODV�HVWmR�HQYROYLGRV�HP�WRGDV�DV�FDUDFWHUtVWLFDV�KXPDQDV�TXH�QRV�
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FKDQQHOV���KWWS���ZZZ�VWNH�RUJ����
C0015.indd 22 04/11/15 1:13 PM
3COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES
23
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UHGX]�D�LQFRUSRUDomR�GH�FDQDLV�GH�FiOFLR�GR�WLSR�1�QD�
PHPEUDQD�SODVPiWLFD���&DS�¬���������
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FDQDLV�L{QLFRV�H�GH�VXDV�IXQo}HV���
 ENZIMAS 
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&RP�IUHTXrQFLD��D�PROpFXOD�GR�IiUPDFR�p�XP�VXEVWUDWR�DQiOR�
JR�TXH�DJH�FRPR�XP�LQLELGRU�FRPSHWLWLYR�GD�HQ]LPD��S�¬H[���R�
�FDSWRSULO���DJLQGR�VREUH�D�HQ]LPD�FRQYHUVRUD�GH�DQJLRWHQVLQD��
�&DS�¬������HP�RXWURV�FDVRV��D�OLJDomR�p�LUUHYHUVtYHO�H�QmR�FRPSH�
WLWLYD��S�¬H[���D��DVSLULQD���DJLQGR�QD�FLFOR�R[LJHQDVH���&DS�¬������2V�
IiUPDFRV�SRGHP�WDPEpP�DJLU�FRPR�IDOVRV�VXEVWUDWRV��HP�TXH�
D�PROpFXOD�GR�IiUPDFR�VRIUH�WUDQVIRUPDo}HV�TXtPLFDV��GDQGR�
RULJHP�D�XP�SURGXWR�DQ{PDOR�TXH�SHUWXUED�D�YLD�PHWDEyOLFD�
QRUPDO��8P�ERP�H[HPSOR�p�R�IiUPDFR�DQWLQHRSOiVLFR��IOXRUX�
UDFLOD���TXH�VXEVWLWXL�D�XUDFLOD�FRPR�LQWHUPHGLiULR�QD�ELRVVtQ�
WHVH�GDV�SXULQDV��PDV�QmR�SRGH�VHU�FRQYHUWLGR�HP�WLPLGLODWR��
EORTXHDQGR��DVVLP��D�VtQWHVH�GR�'1$�H�LPSHGLQGR�D�GLYLVmR�
FHOXODU���&DS�¬������
�'HYH�VH�PHQFLRQDU��WDPEpP��TXH�RV�IiUPDFRV�SRGHP�H[LJLU�
GHJUDGDomR�HQ]LPiWLFD�SDUD�FRQYHUWr�ORV��GH�IRUPD�LQDWLYD��D�
XPD�SUy�GURJD��RX�SUy�IiUPDFR���&DS�¬�����SDUD�D�IRUPD�DWLYD�
�S�¬H[���R��HQDODSULO��p�FRQYHUWLGR�HP�HQDODSULODW�SRU�HVWHUDVHV��
TXH�LQLEHP�D�HQ]LPD�GH�FRQYHUVmR�GD�DQJLRWHQVLQD���$OpP�GLV�
VR��FRPR�GLVFXWLGR�QR��&DStWXOR¬�����D�WR[LFLGDGH�GR�IiUPDFR�IUH�
TXHQWHPHQWH�UHVXOWD�GD�FRQYHUVmR�HQ]LPiWLFD�GD�PROpFXOD�GR�IiUPDFR�SDUD�XP�PHWDEyOLWR�UHDWLYR��2�SDUDFHWDPRO���&DS�¬�����
FDXVD�GDQR�DR�ItJDGR�HP�VXD�YLD��1R�TXH�FRQFHUQH�j�DomR�
SULPiULD�GR�IiUPDFR��HVVH�p�XP�HIHLWR�FRODWHUDO�LQGHVHMiYHO��
PDV�GH�HQRUPH�LPSRUWkQFLD�SUiWLFD���
 TRANSPORTADORES 
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RUJkQLFDV�DWUDYpV�GDV�PHPEUDQDV�FHOXODUHV�RFRUUH�DWUDYpV�
GRV�FDQDLV��DQWHULRUPHQWH��RX�DWUDYpV�GD�DomR�GH�XPD�SURWHtQD�
WUDQVSRUWDGRUD��YLVWR�TXH�DV�HVSpFLHV�SHUPDQHQWHV�VmR��HP�
JHUDO��PXLWR�SRODUHV��LQVXILFLHQWHPHQWH�OLSRVVRO~YHLV��SDUD�
SHQHWUDU�QDV�PHPEUDQDV�OLStGLFDV�SRU�VL�PHVPDV���)LJ�¬����'���
0XLWRV�GHVVHV�WUDQVSRUWDGRUHV�VmR�FRQKHFLGRV��H[HPSORV�GH�
DOJXQV�FRP�LPSRUWkQFLD�IDUPDFROyJLFD�HP�SDUWLFXODU�LQFOXHP�
DTXHOHV�UHVSRQViYHLV�SHOR�WUDQVSRUWH�GH�tRQV�H�PXLWDV�PROpFX�
ODV�RUJkQLFDV�SHOR�W~EXOR�UHQDO��SHOR�HSLWpOLR�LQWHVWLQDO�H�SHOD�
EDUUHLUD�KHPDWRHQFHIiOLFD��R�WUDQVSRUWH�GH�1D����H�&D�����SDUD�IRUD�
GDV�FpOXODV�H�D�FDSWDomR�GRV�SUHFXUVRUHV�GH�QHXURWUDQVPLVVRUHV�
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R�WUDQVSRUWH�GH�PROpFXODV�GH�IiUPDFRV�H�VHXV�PHWDEyOLWRV�DWUD�
YpV�GH�PHPEUDQDV�FHOXODUHV�H�EDUUHLUDV�HSLWHOLDLV��)DODUHPRV�
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WUDQVSRUWH�GH�tRQV��JHUDOPHQWH�1D������DPERV�QD�PHVPD�GLUHomR�
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GHSHQGHQWH�GH�$73��$V�SURWHtQDV�WUDQVSRUWDGRUDV�LQFRUSRUDP�
XP�ORFDO�GH�UHFRQKHFLPHQWR�TXH�DV�WRUQD�HVSHFtILFDV�SDUD�
XPD�HVSpFLH�SDUWLFXODU�D�VHU�WUDQVSRUWDGD��H�HVVHV�ORFDLV�GH�
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Acúmulo de
composto anômalo
Transporte
bloqueado
Inibidor
Falso
substrato
Transporte
normal
RECEPTORES
CANAIS IÔNICOS
ENZIMAS
TRANSPORTADORES
Produto anômaloAgonista/substrato
Antagonista/inibidor Pró-fármaco
Direto
Sem efeito
Mediadores endógenos bloqueados
Antagonista
Agonista/
agonista
inverso Transcrição
do DNA
Modulação de
canais iônicos
Ativação/inibição
enzimática
Abertura/fechamento
de canais iônicos
Mecanismos
de transdução
Aumento ou diminuição
da probabilidade
de abertura
Moduladores
Bloqueio
da permeação
Bloqueadores
Produção de
fármaco ativo
Produção de
metabólito anômalo
Inibição da reação
normal
Inibidor
Pró-fármaco
Falso
substrato
ou
A
B
C
D
 Fig. 3.1 Tipos de alvos para a ação de fármacos. 
C0015.indd 23 04/11/15 1:13 PM
SEÇÃO 1 PRINCÍPIOS GERAIS3
24
 PROTEÍNAS RECEPTORAS 
 CLONAGEM DE RECEPTORES 
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GR�UHFHSWRU��
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SXULILFDGDV��IRL�SRVVtYHO�DQDOLVDU�D�VHTXrQFLD�GH�DPLQRiFLGRV�
GH�XP�SHTXHQR�WUHFKR��SHUPLWLQGR�TXH�D�VHTXrQFLD�EiVLFD�
GR�51$P�IRVVH�GHGX]LGD�H�TXH�XP�'1$�FRPSOHWR�IRVVH�
LVRODGR��SRU�PpWRGRV�GH�FORQDJHP�FRQYHQFLRQDLV��D�FRPHoDU�
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JHQRPD�KXPDQR�GH�YiULDV�HVSpFLHV��LQFOXLQGR�R�VHU�KXPDQR��
WDPEpP�DV�HVWUDWpJLDV�GH�FORQDJHP�FRP�EDVH�QD�KRPRORJLD�GH�
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GD�SURWHtQD�UHFHSWRUD��$VVLP��DWXDOPHQWH�DOJXPDV�FHQWHQDV�
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IRUDP�FORQDGDV��2V�OLJDQWHV�HQGyJHQRV�GH�PXLWRV�GHVVHV�QRYRV�
UHFHSWRUHV�LGHQWLILFDGRV�SHOD�FORQDJHP�JHQpWLFD�SHUPDQHFHP�
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C0015.indd 24 04/11/15 1:13 PM
3COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES
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1.Canais iônicos 
controlados por ligantes 
(receptores ionotrópicos)
2.Receptores acoplados à 
proteína G
(metabotrópicos)
3.Receptores
ligados
a quinases
4.Receptores
nucleares
NÚCLEO
Transcrição
de gene
Transcrição de gene
Efeitos celularesEfeitos celulares
Fosforilação
de proteína
Efeitos celulares
Fosforilação
de proteína
Outro
Liberação
de Ca
2+
Alteração da
excitabilidade
Efeitos celulares
Hiperpolarização 
ou
despolarização
HorasHorasSegundosMilissegundos
Escala de tempo
Segundos mensageiros
R R/E
R
E
G G
ou ou
Íons Íons
Síntese de proteína
Síntese de proteína
Receptor
de estrógenos
Receptores
de citocinas
Receptor muscarínico
da ACh
Receptor nicotínico
da ACh
Exemplos
R R
 Fig. 3.2 Tipos de relação entre receptor e efetor. ACh, acetilcolina; E, enzima; G, proteína G; R, receptor. 
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C0015.indd 25 04/11/15 1:13 PM
SEÇÃO 1 PRINCÍPIOS GERAIS3
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LIGANTES 
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GRPtQLR�LQWUDFHOXODU�HQWUH�RV�GRPtQLRV�WUDQVPHPEUDQDUHV���
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WDPEpP�LQFOXHP�R�*$%$�$��H�RV�UHFHSWRUHV�GH�JOLFLQD���&DS�¬������EHP�FRPR�RV¬UHFHSWRUHV���+7�����&DSV�¬���H¬�����������������([LVWHP�RXWURV�
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DVSHFWRV�GR�UHFHSWRU�QLFRWtQLFR�GH�DFHWLOFROLQD��
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TXH�RV�VHJPHQWRV�0����DEDXODGRV�VH�DIDVWHP�XQV�GRV�RXWURV��SURPRYHQGR��DVVLP��D�DEHUWXUD�GR�FDQDO���0L\D]DZD��HW�DO���¬��������$�ERUGD�GR�FDQDO�FRQ�
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SHUPHiYHO�D�FiWLRQV��LQLFLDOPHQWH��1$����H�.�����HPERUD�DOJXQV�WLSRV�GH�
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Domínio de
ligação ao
DNA (“dedos
de zinco”)
Domínio
catalítico
Domínios
de ligação
Revestimento
do canal
x 4 ou 5
Domínio
de ligação
Domínio de 
acoplamento
à proteína G
Domínio
de ligação
Domínio
de ligação
A
B
C
D
Tipo 3 
Receptores
ligados a 
quinases
Tipo 4 
Receptores
nucleares
Tipo 1 Canais 
iônicos
controlados 
por ligantes 
(receptores
ionotrópicos)
Tipo 2 
Receptores
acoplados à 
proteína G 
(receptores
metabotrópicos)
N
C
N
C
N
C
N
C
 Fig. 3.3 Estrutura geral de quatro famílias de receptores. 
 Os segmentos retangulares representam regiões hidrofóbicas 
 a -helicoidais da proteína compreendendo aproximadamente 
vinte aminoácidos, que formam os domínios transmembrana dos 
receptores. [ A ] Tipo 1: canais iônicos controlados por ligantes. 
O exemplo aqui ilustrado apresenta a estrutura da subunidade 
do receptor nicotínico de acetilcolina. A estrutura da subunidade 
de outros canais iônicos operados por ligantes é apresentada 
na Figura 3.20 . Muitos canais iônicos controlados por ligantes 
compreendem quatro ou cinco subunidades do tipo mostrado, 
e o complexo inteiro contém 16-20 segmentos transmembrana 
circundando um canal iônico central. [ B ] Tipo 2: Receptores 
acoplados à proteína G. [ C ] Tipo 3: receptores ligados a 
quinases. A maior parte dos receptores de fatores de crescimento 
incorpora o domínio de ligação ao ligante e o domínio enzimático 
(quinase) na mesma molécula, como aqui mostrado, enquanto 
os receptores de citocinas não possuem um domínio de quinase 
intracelular, mas se relacionam com moléculas de quinases 
citosólicas. Outras variantes estruturais também existem. [ D ] Tipo 
4: receptores nucleares que controlam a transcrição de genes. 
C0015.indd 26 04/11/15 1:13 PM
3COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES
27
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 TIPO 2: RECEPTORES ACOPLADOS 
À PROTEÍNA G 
�$�JUDQGH�IDPtOLD�*3&5�HQJORED�PXLWRV�GRV�UHFHSWRUHV�TXH�
VmR�IDPLOLDUHV�DRV�IDUPDFRORJLVWDV��FRPR�$&K5�PXVFDUtQLFRV��
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D�PDLRULD�GHOHV��RV�HVWXGRV�IDUPDFROyJLFRV�H�PROHFXODUHV�UHYH�
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HVWUXWXUD�KHSWD�KHOLFRLGDO������
 Tabela 3.1 Os quatro tipos principais de receptores 
Tipo 1: canais iônicos 
controlados por ligantes
Tipo 2: receptores 
acoplados à proteína G
Tipo 3: receptores 
ligados a quinases
Tipo 4: receptores 
nucleares
Localização Membrana Membrana Membrana Intracelular
Efetor Canal iônico Canal ou enzima Proteína quinases Transcrição gênica
Acoplamento Direto Proteína G ou arrestina Direto Via DNA
Exemplos Receptor nicotínico da 
acetilcolina, receptor 
GABA A 
Receptor muscarínico da 
acetilcolina, adrenoceptores
Insulina, fatores de 
crescimento, receptores de 
citocinas
Receptores de esteroides
Estrutura Organização oligomérica 
de subunidades 
circundando um poro 
central
Estrutura monomérica ou 
oligomérica compreendendo 
sete hélices transmembrana 
com um domínio intracelular 
acoplador de proteína G
Hélice transmembrana 
única ligando o domínio 
extracelular do receptor ao 
domínio da quinase
Estrutura monomérica 
com domínios de ligação 
ao receptor e domínios de 
ligação ao DNA
C0015.indd 27 04/11/15 1:13 PM
SEÇÃO 1 PRINCÍPIOS GERAIS3
28
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VXOWDU��+LOO����������
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FRPR�VREUH�DV�LQWHUDo}HV�GRV�UHFHSWRUHV�DFRSODGRV�j�SURWHtQD�
*��$�SDUWLU�GHVVHV�HVWXGRV��p�SRVVtYHO�DIHULU��FRP�PDLRU�FODUH]D��
R�PHFDQLVPR�GH�DWLYDomR�GRV�*3&5V�H�RV�IDWRUHV�GHWHUPLQDQ�WHV�QD�HILFiFLD�GRV�DJRQLVWDV��EHP�FRPR�REWHU�PHOKRUHV�EDVHV�
SDUD�D�FRQFHSomR�GH�QRYRV�OLJDQWHV�*3&5��
�2V�UHFHSWRUHV�DFRSODGRV�j�SURWHtQD�*�FRQVLVWHP�QXPD�~QLFD�
FDGHLD�GH�SROLSHSWtGHRV��QRUPDOPHQWH�GH���������UHVtGXRV��
PDV��HP�DOJXQV�FDVRV��DWLQJLQGR�������UHVtGXRV��$�DQDWRPLD�
JHUDO�p�DSUHVHQWDGD�QD��)LJXUD¬����%��6XD�HVWUXWXUD�HQJORED���
 Canais iônicos regulados por ligantes 
 • São chamados às vezes de receptores ionotrópicos. 
 • Estão envolvidos principalmente na transmissão 
sináptica rápida. 
 • Existem várias famílias estruturais, sendo a mais 
comum a organização heteromérica de quatro ou cinco 
subunidades, com hélices transmembrana dispostas 
em torno de um canal central aquoso. 
 • A ligação do ligante e a abertura do canal ocorrem em 
uma escala de tempo de milissegundos. 
 • Os exemplos incluem os receptores nicotínicos da 
acetilcolina, do GABA tipo A (GABA A ), receptores de 
glutamato (NMDA) e de ATP (P2X). 
����(QWUHWDQWR��RV�H[HPSORV�GH�SURPLVFXLGDGH�HVWmR�DXPHQWDQGR��2V�
KRUP{QLRV�HVWHURLGHV��QRUPDOPHQWH�ILpLV�DRV�UHFHSWRUHV�QXFOHDUHV��
LQWHUDJHP�RFDVLRQDOPHQWH�FRP�FDQDLV�L{QLFRV�H�RXWURV�DOYRV���)DONHQVWHLQ�
�HW�DO���¬��������H�DOJXQV�HLFRVDQRLGHV�DJHP�QRV�UHFHSWRUHV�QXFOHDUHV��EHP�
FRPR�QRV�*3&5V��$�QDWXUH]D�WHP�D�PHQWH�PXLWR�DEHUWD��HPERUD�WDLV�
H[HPSORV�VHMDP�UHVSRQViYHLV�SRU�GHL[DU�RV�IDUPDFRORJLVWDV�DERUUHFLGRV�
H�RV�HVWXGDQWHV�HP�GHVHVSHUR��
A
ACh
ACh
ACh
ACh
α
α
γ
α
β δ
α
β δ
Exterior
Membrana
Citosol
α-Hélices formando a comporta
6 nm
3 nm
2 nm
Poro de ~0,7
nm de diâmetro
B
 Fig. 3.4 Estrutura do receptor nicotínico da acetilcolina 
(um típico canal iônico controlado por ligante). [ A ] Diagrama 
esquemático em visão lateral (acima) e transversal (abaixo). 
As cinco subunidades do receptor ( a 2 , b , g , d ) formam um 
agregado que circunda um poro transmembrana central, cujo 
revestimento é formado pelos segmentos helicoidais M 2 de 
cada subunidade. Esses segmentos contêm predomínio de 
aminoácidos carregados negativamente, o que torna o poro 
seletivo para cátions. Existem dois pontos de ligação para 
acetilcolina na porção extracelular do receptor, na interface 
entre a subunidade a e as subunidades adjacentes. Quando 
ocorre a ligação com a acetilcolina, as a -hélices entortadas ou 
se endireitam ou giram e se afastam, abrindo, assim, o poro do 
canal. [ B ] Imagem de alta resolução que apresenta um esquema 
revisto dos domínios intracelulares. (Painel [A] baseado em 
Unwin N 1993 Nicotinic acetylcholine receptor at 9A resolution. 
J Mol Biol 229, 1.101-1.124, and Unwin N 1995 Acetylcholine 
receptor channel imaged in the open state. Nature 373, 37-43; 
painel [B] reproduzido com autorização de Unwin N 2005 
Refi ned structure of the nicotinic acetylcholine receptor at 4A 
resolution. J Mol Biol 346(4), 967-989.) 
C0015.indd 28 04/11/15 1:13 PM
3COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES
29
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 Tabela 3.2 Famílias de receptores acoplados à proteína G a 
Família Receptores b Características estruturais
A: família da rodopsina O maior grupo. Receptores para a maioria dos 
neurotransmissores aminados, muitos neuropeptídeos, 
purinas, prostanoides, canabinoides etc.
Cauda extracelular (N terminal) curta. O 
ligante liga-se a hélices transmembrana 
(aminas) ou a alças extracelulares (peptídeos)
B: família dos receptores de 
secretina/glucagon
Receptores para hormônios peptídicos, incluindo 
secretina, glucagon, calcitonina
Cauda extracelular intermediária 
incorporando o domínio de ligação ao ligante
C: família do receptor 
metabotrópico de glutamato/
sensor de cálcio
Grupo pequeno. Receptores metabotrópicos de 
glutamato, receptores GABA B , receptores sensíveis 
ao Ca 2+ 
Cauda extracelular longa incorporando o 
domínio de ligação ao ligante
 a Uma quarta família distinta inclui muitos receptores para feromônios, mas nenhum receptor farmacológico. 
 b Para listas completas, consulte www.guidetopharmacology.org . 
����2�UHFHSWRU�VHQVRU�GH�&D�������&RQLJUDYH��HW�DO���¬�������p�XP�*3&5�LQFRPXP�
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N
C
N
CCANAIS
ATIVADOS POR 
LIGANTES
(5, 4 ou 3
subunidades)
Receptores de NMDA
Exemplos: NMDAExemplos: nAChR, GABA
A
,5-HT
3
, IP
3
R, RyR
Receptores de cistina (cys-loop)
Exemplo: P2XR
Receptores P2X
 Fig. 3.5 Arquitetura molecular dos canais iônicos ativados por ligantes. Os retângulos azuis e vermelhos representam as a -hélices 
transmembranares, e os ganchos azuis representam as regiões de formação dos poros P loop . Os receptores cys-loop são pentaméricos. 
Os receptores do tipo NMDA são tetraméricos, e os P2X, triméricos. Receptor 5-HT 3 , 5-hydroxitriptamina tipo 3; receptor GABA A , GABA 
tipo A; IP 3 R, receptor do inositol trifosfato; nAChR, receptor nicotínico de acetilcolina; NMDA, N -metil D-Aspartato; P2XR, receptor de purina 
P2X; RyR, receptor de rianodina. 
C0015.indd 29 04/11/15 1:14 PM
SEÇÃO 1 PRINCÍPIOS GERAIS3
30
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 RECEPTORES ATIVADOS POR PROTEASES 
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 PROTEÍNAS G E SUA FUNÇÃO 
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Exterior da célula
Modulador
alostérico
positivo
Agonista
Membrana
Interior
da célula
 Fig. 3.7 Estrutura do receptor muscarínico M 4 . Imagem 
de alta resolução que apresenta a conformação do receptor 
muscarínico M 4 ligado a um agonista (ortostérico) e também 
a um modulador alostérico positivo. Os cilindros em amarelo 
representam os domínios transmembranares. A extensão total 
dos domínios N- e C- terminal e o terceiro circuito intracelular 
não estão representados. (Cortesia de A Christopoulos.) 
10 ms
3 pA
20 ms
2 pA
0
1
2
18 pS
38 pS
N
ú
m
e
r
o
 
d
e
 
c
a
n
a
i
s
 
a
b
e
r
t
o
s
E
s
t
a
d
o
s
 
d
e
 
c
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n
d
u
t
i
v
i
d
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d
e
Aberturas do canal nicotínico de acetilcolina
Aberturas do canal NMDA
A
B
 Fig. 3.6 Aberturas de canais registradas através da técnica 
de Patch-clamp . [ A ] Canais iônicos ativados por acetilcolina 
na placa motora terminal da rã. A pipeta é pressionada contra a 
superfície da membrana com 10 m mol/l ACh. Os desvios abaixo 
apresentam o fl uxo da corrente através dos canais iônicos na 
zona da membrana em que foi aplicada a pipeta. No fi nal do 
registro, é possível ver a abertura discreta entre os dois canais. 
[ B ] Correntes num único canal receptor de NMDA registradas 
nos neurônios cerebrais na conformação exterior da parte da 
membrana da célula ( patch ). O NMDA foi adicionado ao exterior 
da parte da membrana da célula ( patch ) para ativar o canal. 
O canal abre-se em vários níveis de condutância. Em [ B ] as 
aberturas no nível mais alto de condutância e os encerramentos 
subsequentes são lentos, indicando que um canal está aberto 
(não é provável que dois canais abram e fechem ao mesmo 
tempo), enquanto em [ A ] existem níveis discretos que indicam 
dois canais. (Painel [A] cortesia de D Colquhoun e DC Ogden; 
painel [B] reproduzido com autorização de Cull-Candy SG & 
Usowicz MM 1987 Nature 325, 525-528.) 
C0015.indd 30 04/11/15 1:14 PM
3COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES
31
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 Receptores acoplados à proteína G 
 • São denominados algumas vezes receptores 
metabotrópicos ou receptores com sete domínios 
transmembrana (7-TDM). 
 • As estruturas compreendem sete a -hélices que 
atravessam a membrana, em geral ligadas, formando 
estruturas diméricas. 
 • A terceira alça intracelular interage com a proteína G. 
 • A proteína G é uma proteína de membrana que 
compreende três subunidades ( a , b , g ), com a 
subunidade a apresentando atividade GTPásica. 
 • Quando o trímero se liga a um receptor ocupado por 
um agonista, a subunidade a se liga a GTP, dissocia-se 
e, então, fi ca livre para ativar um efetor (p. ex., uma 
enzima de membrana). Em alguns casos, a subunidade 
 b g é a espécie ativadora. 
 • A ativação do efetor termina quando ocorre a hidrólise 
da molécula de GTP ligada, o que permite que a 
subunidade a se recombine com b g . 
 • Existem vários tipos de proteína G, que interagem com 
diferentes receptores e controlam diferentes efetores. 
 • Exemplos incluem o receptor muscarínico da 
acetilcolina, adrenoceptores, receptores de 
neuropeptídeos e de quimiocinas, e os receptores 
ativados por protease. 
ATIVO DESSENSIBILIZADO
N
Clivagem pela trombina
INATIVO
N
N
Agonista preso
Fosforilação
Fragmento
liberado
P
N
 Fig. 3.8 Ativação de um receptor ativado por protease pela clivagem do domínio N-terminal extracelular. A inativação ocorre por 
fosforilação. A recuperação requer nova síntese do receptor. 
C0015.indd 31 04/11/15 1:14 PM
SEÇÃO 1 PRINCÍPIOS GERAIS3
32
 Tabela 3.3 Os principais subtipos de proteína G e suas funções a 
Subtipos Receptores associados Efetores principais Notas
Subunidades G a 
G a s Muitos receptores para 
aminas e outros (p. ex., 
catecolaminas, histamina, 
serotonina)
Estimula a adenililciclase, aumentando a formação 
de AMPc
Ativadas pela toxina do cólera, 
que bloqueia a atividade GTPase, 
impedindo, assim, a inativação
G a i Como para Ga S , e também 
receptores opioides e 
canabinoides
Inibe a adenililciclase, diminuindo a formação de 
AMPc
Bloqueadas pela toxina pertússis, 
que impede a dissociação do 
complexo a b g 
G a o Como para Ga S , e também 
receptores opioides e 
canabinoides
? Efeitos limitados da subunidade a (os efeitos 
devem-se principalmente às subunidades b g )
Bloqueada pela toxina pertússis. 
Ocorre principalmente no sistema 
nervoso
G a q Receptores de aminas, 
peptídeos e prostanoides
Ativa a fosfolipase C, aumentando a produção 
dos segundos mensageiros inositol trisfosfato e 
diacilglicerol (págs. 34 e 35)
—
Subunidades G b g 
Todos os GPCRs Ativam canais de potássio 
 Inibem canais de cálcio controlados por voltagem 
 Ativam as GPCR quinases (GRKs, pág. 36) 
 Ativam a cascata de proteínas quinases ativadas 
por mitógenos 
 Interage com algumas formas de adenil-ciclase e 
com fosfolipase C b 
Muitas isoformas de b g 
identifi cadas, mas as funções 
específi cas ainda não são 
conhecidas.
 GPCR, receptor acoplado à proteína G ( G-protein-coupled receptor ). 
 a Esta tabela lista apenas as isoformas de maior signifi cância farmacológica. Muitas outras foram identifi cadas, algumas, inclusive, têm 
funções no olfato, paladar, transdução visual e em outras funções fi siológicas ( Offermanns, 2003 ). 
Receptor
GDP GDP
GDP
P
+
GTP
GTP
Estado de repouso
Proteínas-alvo
ativadas
βγα βγ
βγα βγα
Alvo
1
Alvo
2
Alvo
2
Receptor ocupado por um agonista
InativoInativo
AtivoAtivoAtivoAtivo
InativoInativo
GTP hidrolisado
Target
1
Alvo
2
Alvo
1
Alvo
2
α
Alvo
1
 Fig. 3.9 A função da proteína G. A proteína G consiste em três subunidades ( a , b , g ) que fi cam ancoradas à membrana através de 
resíduos de lipídeos fi xos. O acoplamento da subunidade a a um receptor ocupado por um agonista promove a troca do GDP ligado pelo 
GTP intracelular; o complexo a -GTP, então, se dissocia do receptor e do complexo b g , interagindo com uma proteína-alvo (alvo 1, que 
pode ser uma enzima, como adenil-ciclase ou fosfolipase C). O complexo b g também ativa uma proteína-alvo (alvo 2, que pode ser um 
canal iônico ou uma quinase). A atividade GTPase da subunidade a aumenta quando a proteína-alvo é ligada, resultando em hidrólise do 
GTP ligado para GDP, o que faz com que a subunidade a volte a se ligar com b g . 
C0015.indd 32 04/11/15 1:14 PM
3COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES
33
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Enzima-
alvo
Receptor
inibitório
Receptor
estimulatório
G
i
G
s
R
i
R
s
βγ βγαi αs
 Fig. 3.10 Controle bidirecional de 
uma enzima-alvo como a adenilato 
ciclase, por G s e G i . A heterogeneidade 
das proteínas G permite que receptores 
diferentes exerçam efeitos opostos em 
uma mesma enzima-alvo. 
C0015.indd 33 04/11/15 1:14 PM
SEÇÃO 1 PRINCÍPIOS GERAIS3
34
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GR�IRVIDWLGLOLQRVLWRO��������ELVIRVIDWR��3,3������TXH�SRVVXL�JUXSRV�DGLFLRQDLV�GH�IRVIDWR�OLJDGRV�DR�DQHO�LQRVLWRO��GHVHPSHQKD�
SDSHO�FKDYH��2�3,3����p�R�VXEVWUDWR�GH�XPD�HQ]LPD�OLJDGD�j�PHPEUDQD��D�IRVIROLSDVH�&�b���3/&�b����TXH�HIHWXD�VXD�FOLYDJHP�
HP��GLDFLOJOLFHURO���'$*��H��LQRVLWRO�����������WULIRVIDWR���,3������)LJ�¬����������RV�TXDLV�DWXDP�FRPR�VHJXQGRV�PHQVDJHLURV��FRQIRUPH�GLV�
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Lipase (ativa)
ATP 
ADP
Aumento da lipólise
ATP 
ADP
Redução da síntese de glicogênio
ATP 
ADP
ATP 
ADP
Fosforilase
quinase (ativa)
Fosforilase a
(ativa)
ATP 
ADP
Aumento da quebra de glicogênio
Glicogênio
Glicose-1-fosfato
Glicogênio sintase
(inativa)
G
Proteína quinase
(ativa)
Proteína quinase
(inativa)
Lipase (inativa)
Glicogênio
sintase (ativa)
Fosforilase
quinase (inativa)
Fosforilase b
(inativa)
AC
ATP 
AMPc
Agonista
R
 Fig. 3.11 Regulação do metabolismo energético pelo AMPc. AC, adenilil ciclase. 
C0015.indd 34 04/11/15 1:14 PM
3COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES
35
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 OUTROS DESENVOLVIMENTOS NA BIOLOGIA 
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